U.S. patent application number 12/535642 was filed with the patent office on 2009-11-26 for isoindoline compounds and methods of their use.
This patent application is currently assigned to Celgene. Invention is credited to Hon-Wah Man, George W. MULLER.
Application Number | 20090291991 12/535642 |
Document ID | / |
Family ID | 35733185 |
Filed Date | 2009-11-26 |
United States Patent
Application |
20090291991 |
Kind Code |
A1 |
MULLER; George W. ; et
al. |
November 26, 2009 |
ISOINDOLINE COMPOUNDS AND METHODS OF THEIR USE
Abstract
Novel isoindoline compounds are disclosed. Methods of treating,
preventing and/or managing cancer, diseases and disorders
associated with, or characterized by, undesired angiogenesis, and
diseases and disorders mediated by PDE 4, using the compounds are
also disclosed.
Inventors: |
MULLER; George W.;
(Bridgewater, NJ) ; Man; Hon-Wah; (Princeton,
NJ) |
Correspondence
Address: |
JONES DAY
222 E. 41ST. STREET
NEW YORK
NY
10017
US
|
Assignee: |
Celgene
|
Family ID: |
35733185 |
Appl. No.: |
12/535642 |
Filed: |
August 4, 2009 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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12070322 |
Feb 15, 2008 |
7569597 |
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12535642 |
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10900332 |
Jul 28, 2004 |
7405237 |
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12070322 |
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Current U.S.
Class: |
514/364 ;
514/417; 548/143; 548/485 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 31/04 20180101; A61P 1/04 20180101; A61P 35/02 20180101; A61P
43/00 20180101; A61P 35/00 20180101; C07D 413/06 20130101; A61P
31/22 20180101; A61P 9/04 20180101; A61P 15/00 20180101; A61P 27/06
20180101; A61P 29/00 20180101; A61P 9/10 20180101; A61P 11/00
20180101; A61P 33/00 20180101; A61P 3/00 20180101; A61P 9/14
20180101; A61P 17/00 20180101; C07D 405/12 20130101; A61P 9/00
20180101; A61P 1/02 20180101; A61P 13/12 20180101; C07D 209/46
20130101; A61P 7/06 20180101; A61P 19/02 20180101; C07D 209/48
20130101 |
Class at
Publication: |
514/364 ;
548/485; 548/143; 514/417 |
International
Class: |
A61K 31/4245 20060101
A61K031/4245; C07D 209/36 20060101 C07D209/36; C07D 413/00 20060101
C07D413/00; A61K 31/40 20060101 A61K031/40 |
Claims
1-29. (canceled)
30. A compound of formula I: ##STR00019## or a pharmaceutically
acceptable salt, solvate, or stereoisomer thereof, wherein: one of
X.sup.1 and X.sup.2 is amino, nitro, alkyl of one to six carbons,
or NH-Z, and the other of X.sup.1 or X.sup.2 is hydrogen; each of
R.sup.1 and R.sup.2, independent of the other, is hydroxy or NH-Z;
R.sup.3 is hydrogen, alkyl of one to six carbons, halo, or
haloalkyl; Z is, independently at each occurrence, hydrogen, aryl,
alkyl of one to six carbons, formyl, or acyl of one to six carbons;
and n is 0, 1, or 2; provided that if X.sup.1 is amino and n is 1
or 2, then R.sup.1 and R.sup.2 are not both hydroxy.
31. A compound of formula II: ##STR00020## or a pharmaceutically
acceptable salt, solvate, or stereoisomer thereof, wherein one of
X.sup.1 and X.sup.2 is amino, nitro, alkyl of one to six carbons,
or NH-Z, and the other of X.sup.1 or X.sup.2 is hydrogen; each of
R.sup.1 and R.sup.2, independently of the other, is hydroxy or
NH-Z; R.sup.3 is alkyl or one to six carbons, halo, or hydrogen; Z
is, independently at each occurrence, hydrogen, aryl, alkyl of one
to six carbons, or acyl of one to six carbons; and n is 0, 1, or
2.
32. A compound of formula I ##STR00021## or a pharmaceutically
acceptable salt, solvate, or stereoisomer thereof, wherein: one of
X.sup.1 and X.sup.2 is amino, nitro, alkyl of one to six carbons,
or NH-Z, and the other of X.sup.1 or X.sup.2 is hydrogen; each of
R.sup.1 and R.sup.2, independent of the other, is hydroxy or NH-Z;
R.sup.3 is alkyl of one to six carbons, halo, or hydrogen; Z is,
independently at each occurrence, hydrogen, aryl, alkyl of one to
six carbons, acyl of one to six carbons, or furanylalkyl, wherein
the alkyl of the furanylalkyl has one to six carbons; and n is 0,
1, or 2.
33. The compound of claim 30, or a pharmaceutically acceptable
salt, solvate, or stereoisomer thereof, wherein: one of X.sup.1 and
X.sup.2 is nitro or NH-Z and the other of X.sup.1 and X.sup.2 is
hydrogen; each of R.sup.1 and R.sup.2, independent of the other, is
hydroxy or NH-Z; R.sup.3 is alkyl or one to six carbons, halo, or
hydrogen; Z is, independently at each occurrence, hydrogen, phenyl,
acyl of one to six carbons, or alkyl of one to six carbons; and n
is 0, 1, or 2; provided that if one of X.sup.1 and X.sup.2 is
nitro, and n is 1 or 2, then R.sup.1 and R.sup.2 are other than
hydroxy.
34. The compound of claim 30, or a pharmaceutically acceptable
salt, solvate, or stereoisomer thereof, wherein one of X.sup.1 and
X.sup.2 is alkyl of one to six carbons or NH-Z and the other of
X.sup.1 and X.sup.2 is hydrogen; each of R.sup.1 and R.sup.2,
independent of the other, is hydroxy or NH-Z; R.sup.3 is alkyl of
one to six carbons, halo, or hydrogen; Z is, independently at each
occurrence, phenyl, acyl of one to six carbons, or alkyl of one to
six carbons; and n is 0, 1, or 2.
35. A compound of formula III: ##STR00022## or a pharmaceutically
acceptable salt, solvate, or stereoisomer thereof, wherein: Y is
C.dbd.O, CH.sub.2, SO.sub.2, or CH.sub.2C.dbd.O; X is hydrogen or
alkyl of 1 to 4 carbon atoms; (i) each of R.sup.1, R.sup.2,
R.sup.3, and R.sup.4, independently of the others, is hydrogen,
halo, trifluoromethyl, acetyl, alkyl of 1 to 8 carbon atoms, alkoxy
of 1 to 4 carbon atoms, nitro, cyano, hydroxy,
--CH.sub.2NR.sup.9R.sup.9, --(CH.sub.2).sub.2NR.sup.8R.sup.9, or
--NR.sup.8R.sup.9 or (ii) any two of R.sup.1, R.sup.2, R.sup.3, and
R.sup.4 on adjacent carbon atoms, together with the benzene ring to
which they are bound are naphthylidene, quinoline, quinoxaline,
benzimidazole, benzodioxole, or 2-hydroxybenzimidazole; each of
R.sup.5 and R.sup.6, independently of the other, is hydrogen, alkyl
of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon atoms, cyano,
benzocycloalkoxy, cycloalkoxy of up to 18 carbon atoms,
bicycloalkoxy of up to 18 carbon atoms, tricycloalkoxy of up to 18
carbon atoms, or cycloalkylalkoxy of up to 18 carbon atoms; (i)
each of R.sup.8 and R.sup.9, independently of the other, is
hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl,
pyridylmethyl, or (ii) one of R.sup.8 and R.sup.9 is hydrogen and
the other is --OR.sup.10 or --SO.sub.2R.sup.10, wherein R.sup.10 is
hydrogen, alkyl of 1 to 8 carbon atoms, cycloalkyl,
cycloalkylmethyl of up to 6 carbon atoms, phenyl, pyridyl, benzyl,
imidazolylmethyl, pyridylmethyl, NR.sup.11R.sup.12, or
CH.sub.2NR.sup.14R.sup.15, wherein R.sup.11 and R.sup.12,
independently of each other, are hydrogen, alkyl of 1 to 8 carbon
atoms, phenyl, or benzyl and R.sup.14 and R.sup.15, independently
of each other, are hydrogen, methyl, ethyl, or propyl; or (iii)
R.sup.8 and R.sup.9, taken together are tetramethylene,
pentamethylene, hexamethylene, --CH.dbd.NCH.dbd.CH--, or
--CH.sub.2CH.sub.2X.sup.1CH.sub.2CH.sub.2-- in which X.sup.1 is
--O--, --S--, or --NH--.
36. A pharmaceutical composition comprising a compound of claim 30,
31, 32, or 35.
Description
1. FIELD OF THE INVENTION
[0001] This invention relates to novel isoindoline compounds and
their use in methods of treating, preventing and/or managing
cancer, and other diseases and disorders including, but not limited
to, those associated with, or characterized by, undesired
angiogenesis and/or those mediated by PDE 4 inhibition.
2. BACKGROUND OF THE INVENTION
2.1 Pathobiology of Cancer and Other Diseases
[0002] Cancer is characterized primarily by an increase in the
number of abnormal cells derived from a given normal tissue,
invasion of adjacent tissues by these abnormal cells, or lymphatic
or blood-borne spread of malignant cells to regional lymph nodes
and to distant sites (metastasis). Clinical data and molecular
biologic studies indicate that cancer is a multistep process that
begins with minor preneoplastic changes, which may under certain
conditions progress to neoplasia. The neoplastic lesion may evolve
clonally and develop an increasing capacity for invasion, growth,
metastasis, and heterogeneity, especially under conditions in which
the neoplastic cells escape the host's immune surveillance. Roitt,
I., Brostoff, J and Kale, D., Immunology, 17.1-17.12 (3rd ed.,
Mosby, St. Louis, Mo., 1993).
[0003] There is an enormous variety of cancers which are described
in detail in the medical literature. Examples includes cancer of
the lung, colon, rectum, prostate, breast, brain, and intestine.
The incidence of cancer continues to climb as the general
population ages, as new cancers develop, and as susceptible
populations (e.g., people infected with AIDS or excessively exposed
to sunlight) grow. A tremendous demand therefore exists for new
methods and compositions that can be used to treat patients with
cancer.
[0004] Many types of cancers are associated with new blood vessel
formation, a process known as angiogenesis. Several of the
mechanisms involved in tumor-induced angiogenesis have been
elucidated. The most direct of these mechanisms is the secretion by
the tumor cells of cytokines with angiogenic properties. Examples
of these cytokines include acidic and basic fibroblastic growth
factor (a,b-FGF), angiogenin, vascular endothelial growth factor
(VEGF), and TNF-.alpha. Alternatively, tumor cells can release
angiogenic peptides through the production of proteases and the
subsequent breakdown of the extracellular matrix where some
cytokines are stored (e.g., b-FGF). Angiogenesis can also be
induced indirectly through the recruitment of inflammatory cells
(particularly macrophages) and their subsequent release of
angiogenic cytokines (e.g., TNF-.alpha., bFGF).
[0005] A variety of other diseases and disorders are also
associated with, or characterized by, undesired angiogenesis. For
example, enhanced or unregulated angiogenesis has been implicated
in a number of diseases and medical conditions including, but not
limited to, ocular neovascular diseases, choroidal neovascular
diseases, retina neovascular diseases, rubeosis (neovascularization
of the angle), viral diseases, genetic diseases, inflammatory
diseases, allergic diseases, and autoimmune diseases. Examples of
such diseases and conditions include, but are not limited to:
diabetic retinopathy; retinopathy of prematurity; corneal graft
rejection; neovascular glaucoma; retrolental fibroplasia; and
proliferative vitreoretinopathy.
[0006] Accordingly, compounds that can control angiogenesis or
inhibit the production of certain cytokines, including TNF-.alpha.,
may be useful in the treatment and prevention of various diseases
and conditions.
2.2 Methods of Treatment
[0007] Current cancer therapy may involve surgery, chemotherapy,
hormonal therapy and/or radiation treatment to eradicate neoplastic
cells in a patient (see, for example, Stockdale, 1998, Medicine,
vol. 3, Rubenstein and Federman, eds., Chapter 12, Section IV).
Recently, cancer therapy could also involve biological therapy or
immunotherapy. All of these approaches pose significant drawbacks
for the patient. Surgery, for example, may be contraindicated due
to the health of a patient or may be unacceptable to the patient.
Additionally, surgery may not completely remove neoplastic tissue.
Radiation therapy is only effective when the neoplastic tissue
exhibits a higher sensitivity to radiation than normal tissue.
Radiation therapy can also often elicit serious side effects.
Hormonal therapy is rarely given as a single agent. Although
hormonal therapy can be effective, it is often used to prevent or
delay recurrence of cancer after other treatments have removed the
majority of cancer cells. Biological therapies and immunotherapies
are limited in number and may produce side effects such as rashes
or swellings, flu-like symptoms, including fever, chills and
fatigue, digestive tract problems or allergic reactions.
[0008] With respect to chemotherapy, there are a variety of
chemotherapeutic agents available for treatment of cancer. A
majority of cancer chemotherapeutics act by inhibiting DNA
synthesis, either directly, or indirectly by inhibiting the
biosynthesis of deoxyribonucleotide triphosphate precursors, to
prevent DNA replication and concomitant cell division. Gilman et
al., Goodman and Gilman's: The Pharmacological Basis of
Therapeutics, Tenth Ed. (McGraw Hill, N.Y.).
[0009] Despite availability of a variety of chemotherapeutic
agents, chemotherapy has many drawbacks. Stockdale, Medicine, vol.
3, Rubenstein and Federman, eds., ch. 12, sect. 10, 1998. Almost
all chemotherapeutic agents are toxic, and chemotherapy causes
significant, and often dangerous side effects including severe
nausea, bone marrow depression, and immunosuppression.
Additionally, even with administration of combinations of
chemotherapeutic agents, many tumor cells are resistant or develop
resistance to the chemotherapeutic agents. In fact, those cells
resistant to the particular chemotherapeutic agents used in the
treatment protocol often prove to be resistant to other drugs, even
if those agents act by different mechanism from those of the drugs
used in the specific treatment. This phenomenon is referred to as
pleiotropic drug or multidrug resistance. Because of the drug
resistance, many cancers prove refractory to standard
chemotherapeutic treatment protocols.
[0010] Other diseases or conditions associated with, or
characterized by, undesired angiogenesis are also difficult to
treat. However, some compounds such as protamine, hepain and
steroids have been proposed to be useful in the treatment of
certain specific diseases. Taylor et al., Nature 297:307 (1982);
Folkman et al., Science 221:719 (1983); and U.S. Pat. Nos.
5,001,116 and 4,994,443. Thalidomide and certain derivatives of it
have also been proposed for the treatment of such diseases and
conditions. U.S. Pat. Nos. 5,593,990, 5,629,327, 5,712,291,
6,071,948 and 6,114,355 to D'Amato. Additional compounds that are
reportedly effective are described by U.S. Pat. Nos. 6,380,239 and
6,326,388, both of which are incorporated in their entirety by
reference.
[0011] Still, there is a significant need for safe and effective
methods of treating, preventing and managing cancer and other
diseases and conditions, particularly for diseases that are
refractory to standard treatments, such as surgery, radiation
therapy, chemotherapy and hormonal therapy, while reducing or
avoiding the toxicities and/or side effects associated with the
conventional therapies.
2.3 PDE 4
[0012] Adenosine 3',5'-cyclic monophosphate (cAMP) is another
enzyme that plays a role in many diseases and conditions, such as,
but not limited to asthma and inflammation (Lowe and Cheng, Drugs
of the Future, 17(9), 799-807, 1992). The elevation of cAMP in
inflammatory leukocytes reportedly inhibits their activation and
the subsequent release of inflammatory mediators, including
TNF-.alpha. and nuclear factor .kappa.B (NF-.kappa.B). Increased
levels of cAMP also lead to the relaxation of airway smooth
muscle.
[0013] It is believed that primary cellular mechanism for the
inactivation of cAMP is the breakdown of cAMP by a family of
isoenzymes referred to as cyclic nucleotide phosphodiesterases
(PDE) (Beavo and Reitsnyder, Trends in Pharm., 11, 150-155, 1990).
There are twelve known members of the family of PDEs. It is
recognized that the inhibition of PDE type IV (PDE4) is
particularly effective in both the inhibition of inflammatory
mediated release and the relaxation of airway smooth muscle
(Verghese, et al., Journal of Pharmacology and Experimental
Therapeutics, 272(3), 1313-1320, 1995). Thus, compounds that
specifically inhibit PDE 4 may inhibit inflammation and aid the
relaxation of airway smooth muscle with a minimum of unwanted side
effects, such as cardiovascular or anti-platelet effects.
[0014] The PDE 4 family that is specific for cAMP is currently the
largest, and is composed of at least 4 isozymes (a-d), and multiple
splice variants (Houslay, M. D. et al. in Advances in Pharmacology
44, eds. J. August et al., p. 225, 1998). There may be over 20 PDE
4 isoforms expressed in a cell specific pattern regulated by a
number of different promoters. Disease states for which selective
PDE4 inhibitors have been sought include: asthma, atopic
dermatitis, depression, reperfusion injury, septic shock, toxic
shock, endotoxic shock, adult respiratory distress syndrome,
autoimmune diabetes, diabetes insipidus, multi-infarct dementia,
AIDS, cancer, Crohn's disease, multiple sclerosis, cerebral
ischemia, psoriasis, allograft rejection, restenosis, ulceratiave
colitis, cachexia, cerebral malaria, allergic rhino-conjunctivitis,
osteoarthritis, rheumatoid arthritis, chronic obstructive pulmonary
disease (COPD), chronic bronchitis, cosinophilic granuloma, and
autoimmune encephalomyelitis (Houslay et al., 1998). PDE 4 is
present in the brain and major inflammatory cells and has been
found in abnormally elevated levels in a number of diseases
including atopic dermatitis or eczema, asthma, and hay fever among
others (reference OHSU flyer and J. of Allergy and Clinical
Immunology, 70: 452-457, 1982 by Grewe et al.). In individuals
suffering from atopic diseases elevated PDE 4 activity is found in
their peripheral blood mononuclear leukocytes, T cells, mast cells,
neutrophils and basophils. This increased PDE activity decreases
cAMP levels and results in a breakdown of cAMP control in these
cells. This results in increased immune responses in the blood and
tissues of those that are affected.
[0015] Some PDE 4 inhibitors reportedly have a broad spectrum of
anti-inflammatory activity, with impressive activity in models of
asthma, chronic obstructive pulmonary disorder (COPD) and other
allergic disorders such as atopic dermatitis and hay fever. PDE 4
inhibitors that have been used include theophylline, rolipram,
denbufylline, ARIFLO, ROFLUMILAST, CDP 840 (a tri-aryl ethane) and
CP80633 (a pyrimidone). PDE 4 inhibitors have been shown to
influence eosinophil responses, decrease basophil histamine
release, decrease IgE, PGE2, IL10 synthesis, and decrease anti-CD3
stimulated Il-4 production. Similarly, PDE4 inhibitors have been
shown to block neutrophil functions. Neutrophils play a major role
in asthma, chronic obstructive pulmonary disorder (COPD) and other
allergic disorders. PDE 4 inhibitors have been shown to inhibit the
release of adhesion molecules, reactive oxygen species, interleukin
(IL)-8 and neutrophil elastase, associated with neutrophils which
disrupt the architecture of the lung and therefore airway function.
PDE 4 inhibitors influence multiple functional pathways, act on
multiple immune and inflammatory pathways, and influence synthesis
or release of numerous immune mediators. J. M. Hanifin and S. C.
Chan, "Atopic Dermatitis-Therapeutic Implication for New
Phosphodiesterase Inhibitors," Monocyte Dysregulation of T Cells in
AACI News, 7/2, 1995; J. M. Hanifin et al., "Type 4
Phosphodiesterase Inhibitors Have clinical and In Vitro
Anti-inflammatory Effects in Atopic Dermatitis," Journal of
Investigative Dermatology, 1996, 107, pp 51-56).
[0016] Some of the first generation of PDE 4 inhibitors are
effective in inhibiting PDE4 activity and alleviating a number of
the inflammatory problems caused by over expression of this enzyme.
However, their effectiveness is limited by side effects,
particularly when used systemically, such as nausea and vomiting.
Huang et al., Curr. Opin. In Chem. Biol. 2001, 5:432-438. Indeed,
many of the PDE 4 inhibitors developed to date have been small
molecule compounds with central nervous system and gastrointestinal
side effects, e.g., headache, nausea/emesis, and gastric
secretion.
3. SUMMARY OF THE INVENTION
[0017] This invention encompasses novel isoindoline compounds and
pharmaceutically acceptable salts, solvates, prodrugs, and
stereoisomers thereof.
[0018] This invention also encompasses methods of treating and
preventing cancer. This invention also encompasses methods of
treating and preventing certain types of cancer, including primary
and metastatic cancer, as well as cancers that are refractory or
resistant to conventional chemotherapy. The methods comprise
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
compound of this invention, or a pharmaceutically acceptable salt,
solvate, stereoisomer, or prodrug thereof.
[0019] The invention also encompasses methods of managing cancer
(e.g., preventing or prolonging their recurrence, or lengthening
the time of remission), which comprise administering to a patient
in need of such management a prophylactically effective amount of a
compound of this invention, or a pharmaceutically acceptable salt,
solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
[0020] In particular methods of the invention, a compound of the
invention is administered in combination with a therapy
conventionally used to treat, prevent or manage cancer. Examples of
such conventional therapies include, but are not limited to,
surgery, chemotherapy, radiation therapy, hormonal therapy,
biological therapy and immunotherapy.
[0021] This invention also encompasses methods of treating,
managing and preventing diseases and disorders other than cancer
that are associated with, or characterized by, undesired
angiogenesis, which comprise administering to a patient in need of
such treatment, management or prevention a therapeutically or
prophylactically effective amount of a compound of this invention,
or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof.
[0022] This invention also encompasses methods of treating,
managing and preventing diseases and disorders mediated by PDE 4,
which comprise administering to a patient in need of such
treatment, management or prevention a therapeutically or
prophylactically effective amount of a compound of this invention,
or a pharmaceutically acceptable salt, solvate, hydrate,
stereoisomer, clathrate, or prodrug thereof.
[0023] In other methods of the invention, a compound of the
invention is administered in combination with a therapy
conventionally used to treat, prevent or manage diseases or
disorders associated with, or characterized by, undesired
angiogenesis or mediated by PDE 4. Examples of such conventional
therapies include, but are not limited to, surgery, chemotherapy,
radiation therapy, hormonal therapy, biological therapy and
immunotherapy.
[0024] This invention encompasses pharmaceutical compositions,
single unit dosage forms, dosing regimens and kits which comprise a
compound of this invention, and optionally a second, or additional,
active agent. Second active agents include specific combinations,
or "cocktails," of drugs.
4. DETAILED DESCRIPTION OF THE INVENTION
[0025] This invention encompasses novel isoindoline compounds
described herein, and pharmaceutically acceptable salts, solvates,
prodrugs, and stereoisomers thereof.
[0026] Another embodiment of the invention encompasses methods of
treating, managing, or preventing cancer which comprises
administering to a patient in need of such treatment or prevention
a therapeutically or prophylactically effective amount of a
compound of the invention, or a pharmaceutically acceptable salt,
solvate, hydrate, stereoisomer, clathrate, or prodrug thereof.
[0027] In particular methods encompassed by this embodiment, a
compound of this invention is administered in combination with
another pharmacologically active agent ("second active agent") or
in conjunction with another method of treating, managing, or
preventing cancer. Methods, or therapies, that can be used in
combination with the administration of a compound of this invention
include, but are not limited to, surgery, blood transfusions,
immunotherapy, biological therapy, radiation therapy, and other
non-drug based therapies presently used to treat, prevent or manage
cancer.
[0028] Another embodiment of the invention encompasses methods of
treating, managing or preventing diseases and disorders other than
cancer that are characterized by undesired angiogenesis. These
methods comprise the administration of a therapeutically or
prophylactically effective amount of a compound of the
invention.
[0029] Examples of diseases and disorders associated with, or
characterized by, undesired angiogenesis include, but are not
limited to, inflammatory diseases, autoimmune diseases, viral
diseases, genetic diseases, allergic diseases, bacterial diseases,
ocular neovascular diseases, choroidal neovascular diseases, retina
neovascular diseases, and rubeosis (neovascularization of the
angle). Specific examples of the diseases and disorders associated
with, or characterized by, undesired angiogenesis include, but are
not limited to, endometriosis, Crohn's disease, heart failure,
advanced heart failure, renal impairment, endotoxemia, toxic shock
syndrome, osteoarthritis, retrovirus replication, wasting,
meningitis, silica-induced fibrosis, asbestos-induced fibrosis,
veterinary disorder, malignancy-associated hypercalcemia, stroke,
circulatory shock, periodontitis, gingivitis, macrocytic anemia,
refractory anemia, and 5q-syndrome.
[0030] Another embodiment of this invention encompasses methods of
inhibiting or reducing PDE 4 comprising contacting a compound of
this invention with PDE 4. This invention also encompasses methods
of inhibiting or reducing the level or activity of PDE 4 in a
patient (e.g., human) comprising administering a compound of this
invention to the patient. This invention also encompasses methods
of treating, managing or preventing diseases and disorders mediated
by PDE 4, which comprise the administration of a therapeutically or
prophylactically effective amount of a compound of the
invention.
[0031] Examples of diseases or disorders mediated by PDE 4 include,
but are not limited to, asthma, atopic dermatitis, depression,
reperfusion injury, septic shock, toxic shock, endotoxic shock,
adult respiratory distress syndrome, autoimmune diabetes, diabetes
insipidus, multi-infarct dementia, AIDS, cancer, Crohn's disease,
multiple sclerosis, cerebral ischemia, psoriasis, allograft
rejection, restenosis, ulceratiave colitis, cachexia, cerebral
malaria, allergic rhino-conjunctivitis, osteoarthritis, rheumatoid
arthritis, chronic obstructive pulmonary disease (COPD), chronic
bronchitis, cosinophilic granuloma, and autoimmune
encephalomyelitis.
[0032] In particular methods encompassed by this embodiment, a
compound of the invention is administered in combination with a
second active agent, or in addition to other methods of treating,
managing, or preventing the disease or condition. Second active
agents include small molecules and large molecules (e.g., proteins
and antibodies), examples of which are provided herein, as well as
stem cells. Methods, or therapies, that can be used in combination
with the administration of a compound of this invention include,
but are not limited to, surgery, blood transfusions, immunotherapy,
biological therapy, radiation therapy, and other non-drug based
therapies presently used to treat, prevent or manage disease and
conditions associated with, or characterized by, undesired
angiogenesis.
[0033] The invention also encompasses pharmaceutical compositions
(e.g., single unit dosage forms) that can be used in methods
disclosed herein. Particular pharmaceutical compositions comprise a
compound of the invention and optionally a second active agent.
4.1 Compounds of the Invention
[0034] This invention encompasses novel isoindoline compounds, and
pharmaceutically acceptable salts, solvates, prodrugs, and
stereoisomers thereof, which are described herein.
[0035] In one embodiment, this invention encompasses compounds of
formula I, and pharmaceutically acceptable salts, solvates,
prodrugs, and stereoisomers thereof:
##STR00001##
in which the carbon atom designated C* constitutes a center of
chirality (when n is not zero and R.sup.1 is not the same as
R.sup.2); one of X.sup.1 and X.sup.2 is amino, nitro, alkyl of one
to six carbons, or NH-Z, and the other of X.sup.1 or X.sup.2 is
hydrogen; each of R.sup.1 and R.sup.2 independent of the other, is
hydroxy or NH-Z; R.sup.3 is hydrogen, alkyl of one to six carbons,
halo, or haloalkyl; Z is hydrogen, aryl, alkyl of one to six
carbons, formyl, or acyl of one to six carbons; and n has a value
of 0, 1, or 2; provided that if X.sup.1 is amino, and n is 1 or 2,
then R.sup.1 and R.sup.2 are not both hydroxy.
[0036] In another embodiment, this invention encompasses compounds
of formula II, and pharmaceutically acceptable salts, solvates,
prodrugs, and stereoisomers thereof:
##STR00002##
in which the carbon atom designated C* constitutes a center of
chirality when n is not zero and R.sup.1 is not R.sup.2; one of
X.sup.1 and X.sup.2 is amino, nitro, alkyl of one to six carbons,
or NH-Z, and the other of X.sup.1 or X.sup.2 is hydrogen; each of
R.sup.1 and R.sup.2 independent of the other, is hydroxy or NH-Z;
R.sup.3 is alkyl of one to six carbons, halo, or hydrogen; Z is
hydrogen, aryl or an alkyl or acyl of one to six carbons; and n has
a value of 0, 1, or 2.
[0037] Specific examples include, but are not limited to,
2-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric
acid and
4-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-cabamoyl-butyric
acid, which have the following structures, respectively, and
pharmaceutically acceptable salts, solvates, prodrugs, and
stereoisomers thereof:
##STR00003##
[0038] Other representative compounds are of formula:
##STR00004##
in which the carbon atom designated C* constitutes a center of
chirality when n is not zero and R.sup.1 is not R.sup.2; one of
X.sup.1 and X.sup.2 is amino, nitro, alkyl of one to six carbons,
or NH-Z, and the other of X.sup.1 or X.sup.2 is hydrogen; each of
R.sup.1 and R.sup.2 independent of the other, is hydroxy or NH-Z;
R.sup.3 is alkyl of one to six carbons, halo, or hydrogen; Z is
hydrogen, aryl, an alkyl or acyl of one to six carbons, or
furanylalkyl, wherein the alkyl has one to six carbons; and n has a
value of 0, 1, or 2; and the pharmaceutically acceptable salts,
solvates, prodrugs, and stereoisomers thereof.
[0039] Specific examples include, but are not limited to,
4-carbamoyl-4-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoind-
ol-2-yl}-butyric acid,
4-carbamoyl-2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoind-
ol-2-yl}-butyric acid,
2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-4-p-
henylcarbamoyl-butyric acid, and
2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-pen-
tanedioic acid, which have the following structures, respectively,
and pharmaceutically acceptable salts, solvate, prodrugs, and
stereoisomers thereof:
##STR00005##
[0040] Other specific examples of the compounds are of formula:
##STR00006##
[0041] wherein one of X.sup.1 and X.sup.2 is nitro, or NH-Z, and
the other of X.sup.1 or X.sup.2 is hydrogen;
[0042] each of R.sup.1 and R.sup.2, independent of the other, is
hydroxy or NH-Z;
[0043] R.sup.3 is alkyl of one to six carbons, halo, or
hydrogen;
[0044] Z is hydrogen, phenyl, an acyl of one to six carbons, or an
alkyl of one to six carbons; and
[0045] n has a value of 0, 1, or 2;
[0046] provided that if one of X.sup.1 and X.sup.2 is nitro, and n
is 1 or 2, then R.sup.1 and R.sup.2 are other than hydroxy; and
[0047] if --COR.sup.1 and --(CH.sub.2).sub.nCOR.sup.2 are
different, the carbon atom designated C* constitutes a center of
chirality. Other representative compounds are of formula:
##STR00007##
[0048] wherein one of X.sup.1 and X.sup.2 is alkyl of one to six
carbons;
[0049] each of R.sup.1 and R.sup.2, independent of the other, is
hydroxy or NH-Z;
[0050] R.sup.3 is alkyl of one to six carbons, halo, or
hydrogen;
[0051] Z is hydrogen, phenyl, an acyl of one to six carbons, or an
alkyl of one to six carbons; and
[0052] n has a value of 0, 1, or 2; and
if --COR.sup.1 and --(CH.sub.2).sub.nCOR.sup.2 are different, the
carbon atom designated C* constitutes a center of chirality.
[0053] In another embodiment, this invention encompasses compounds
of formula III, and pharmaceutically acceptable salts, solvates,
prodrugs, and stereoisomers thereof:
##STR00008##
[0054] wherein:
[0055] the carbon atom designated* constitutes a center of
chirality;
[0056] Y is C.dbd.O, CH.sub.2, SO.sub.2 or CH.sub.2C.dbd.O;
[0057] X is hydrogen, or alkyl of 1 to 4 carbon atoms;
[0058] (i) each of R.sup.1, R.sup.2, R.sup.3, and R.sup.4,
independently of the others, is hydrogen, halo, trifluoromethyl,
acetyl, alkyl of 1 to 8 carbon atoms, alkoxy of 1 to 4 carbon
atoms, nitro, cyano, hydroxy, --CH.sub.2NR.sup.8R.sup.9,
--(CH.sub.2).sub.2NR.sup.8R.sup.9, or --NR.sup.8R.sup.9 or
[0059] (ii) any two of R.sup.1, R.sup.2, R.sup.3, and R.sup.4 on
adjacent carbon atoms, together with the depicted benzene ring to
which they are bound are naphthylidene, quinoline, quinoxaline,
benzimidazole, benzodioxole or 2-hydroxybenzimidazole;
[0060] each of R.sup.5 and R.sup.6, independently of the other, is
hydrogen, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 6 carbon
atoms, cyano, benzocycloalkoxy, cycloalkoxy of up to 18 carbon
atoms, bicyloalkoxy of up to 18 carbon atoms, tricylcoalkoxy of up
to 18 carbon atoms, or cycloalkylalkoxy of up to 18 carbon
atoms;
[0061] (i) each of R.sup.8 and R.sup.9, independently of the other,
is hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, benzyl, pyridyl,
pyridylmethyl, or
[0062] (ii) one of R.sup.8 and R.sup.9 is hydrogen and the other is
--COR.sup.10, or --SO.sub.2R.sup.10, in which R.sup.10 is hydrogen,
alkyl of 1 to 8 carbon atoms, cycloalkyl, cycloalkylmethyl of up to
6 carbon atoms, phenyl, pyridyl, benzyl, imidazolylmethyl,
pyridylmethyl, NR.sup.11R.sup.12, or CH.sub.2NR.sup.14R.sup.15,
wherein R.sup.11 and R.sup.12, independently of each other, are
hydrogen, alkyl of 1 to 8 carbon atoms, phenyl, or benzyl and
R.sup.14 and R.sup.15, independently of each other, are hydrogen,
methyl, ethyl, or propyl; or
(iii) R.sup.8 and R.sup.9 taken together are tetramethylene,
pentamethylene, hexamethylene, --CH.dbd.NCH.dbd.CH--, or
--CH.sub.2CH.sub.2X.sup.1CH.sub.2CH.sub.2-- in which X.sup.1 is
--O--, --S--, or --NH--.
[0063] Specific examples include, but are not limited to,
cyclopropanecarboxylic acid
{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-[1,3,4]oxadiazol-2-yl-ethyl]-3-oxo-2,-
3-dihydro-1H-isoindol-4-yl}-amide, which has the following chemical
structure, and pharmaceutically acceptable salts, solvates,
prodrugs, and stereoisomers thereof:
##STR00009##
[0064] As used herein and unless otherwise indicated, the term
"pharmaceutically acceptable salt" encompasses non-toxic acid and
base addition salts of the compound to which the term refers.
Acceptable non-toxic acid addition salts include those derived from
organic and inorganic acids or bases known in the art, which
include, for example, hydrochloric acid, hydrobromic acid,
phosphoric acid, sulfuric acid, methanesulphonic acid, acetic acid,
tartaric acid, lactic acid, succinic acid, citric acid, malic acid,
maleic acid, sorbic acid, aconitic acid, salicylic acid, phthalic
acid, embolic acid, enanthic acid, and the like.
[0065] Compounds that are acidic in nature are capable of forming
salts with various pharmaceutically acceptable bases. The bases
that can be used to prepare pharmaceutically acceptable base
addition salts of such acidic compounds are those that form
non-toxic base addition salts, i.e., salts containing
pharmacologically acceptable cations such as, but not limited to,
alkali metal or alkaline earth metal salts and the calcium,
magnesium, sodium or potassium salts in particular. Suitable
organic bases include, but are not limited to,
N,N-dibenzylethylenediamine, chloroprocaine, choline,
diethanolamine, ethylenediamine, meglumaine (N-methylglucamine),
lysine, and procaine.
[0066] Neutral forms of some compounds may be regenerated by
contacting the salt with a base or acid and isolating the parent
compound in the conventional manner. The parent form of a compound
can differ from its various salt forms in certain physical
properties, such as solubility in polar solvents, but the salts are
typically equivalent to the parent form of the compound for the
purposes of the present invention.
[0067] As used herein and unless otherwise indicated, the term
"prodrug" means a derivative of a compound that can hydrolyze,
oxidize, or otherwise react under biological conditions (in vitro
or in vivo) to provide the compound. Examples of prodrugs include,
but are not limited to, derivatives of compounds of this invention
that comprise biohydrolyzable moieties such as biohydrolyzable
amides, biohydrolyzable esters, biohydrolyzable carbamates,
biohydrolyzable carbonates, biohydrolyzable ureides, and
biohydrolyzable phosphate analogues. Other examples of prodrugs
include derivatives of a compound of this invention that comprise
--NO, --NO.sub.2, --ONO, or --ONO.sub.2 moieties. Prodrugs can
typically be prepared using well-known methods, such as those
described in 1 Burger's Medicinal Chemistry and Drug Discovery,
172-178, 949-982 (Manfred E. Wolff ed., 5th ed. 1995), and Design
of prodrugs (H. Bundgaard ed., Elselvier, N.Y. 1985).
[0068] As used herein and unless otherwise indicated, the terms
"biohydrolyzable amide," "biohydrolyzable ester," "biohydrolyzable
carbamate," "biohydrolyzable carbonate," "biohydrolyzable ureide,"
and "biohydrolyzable phosphate" mean an amide, ester, carbamate,
carbonate, ureide, or phosphate, respectively, of a compound that
either: 1) does not interfere with the biological activity of the
compound but can confer upon that compound advantageous properties
in vivo, such as uptake, duration of action, or onset of action; or
2) is biologically inactive but is converted in vivo to the
biologically active compound. Examples of biohydrolyzable esters
include, but are not limited to, lower alkyl esters, lower
acyloxyalkyl esters (such as acetoxylmethyl, acetoxyethyl,
aminocarbonyloxymethyl, pivaloyloxymethyl, and pivaloyloxyethyl
esters), lactonyl esters (such as phthalidyl and thiophthalidyl
esters), lower alkoxyacyloxyalkyl esters (such as
methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and
isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline
esters, and acylamino alkyl esters (such as acetamidomethyl
esters). Examples of biohydrolyzable amides include, but are not
limited to, lower alkyl amides, .alpha.-amino acid amides,
alkoxyacyl amides, and alkylaminoalkylcarbonyl amides. Examples of
biohydrolyzable carbamates include, but are not limited to, lower
alkylamines, substituted ethylenediamines, aminoacids,
hydroxyalkylamines, heterocyclic and heteroaromatic amines, and
polyether amines.
[0069] Various compounds of the invention contain one or more
chiral centers, and can exist as racemic mixtures of enantiomers or
mixtures of diastereomers. This invention encompasses the use of
stereomerically pure forms of such compounds, as well as the use of
mixtures of those forms. For example, mixtures comprising equal or
unequal amounts of the enantiomers of compounds of this invention
may be used in methods and compositions of the invention. The
purified (R) or (S) enantiomers of the specific compounds disclosed
herein may be used substantially free of its other enantiomer.
[0070] As used herein and unless otherwise indicated, the term
"stereomerically pure" means a composition that comprises one
stereoisomer of a compound and is substantially free of other
stereoisomers of that compound. For example, a stereomerically pure
composition of a compound having one chiral center will be
substantially free of the opposite enantiomer of the compound. A
stereomerically pure composition of a compound having two chiral
centers will be substantially free of other diastereomers of the
compound. A typical stereomerically pure compound comprises greater
than about 80% by weight of one stereoisomer of the compound and
less than about 20% by weight of other stereoisomers of the
compound, more preferably greater than about 90% by weight of one
stereoisomer of the compound and less than about 10% by weight of
the other stereoisomers of the compound, even more preferably
greater than about 95% by weight of one stereoisomer of the
compound and less than about 5% by weight of the other
stereoisomers of the compound, and most preferably greater than
about 97% by weight of one stereoisomer of the compound and less
than about 3% by weight of the other stereoisomers of the
compound.
[0071] As used herein and unless otherwise indicated, the term
"stereomerically enriched" means a composition that comprises
greater than about 60% by weight of one stereoisomer of a compound,
preferably greater than about 70% by weight, more preferably
greater than about 80% by weight of one stereoisomer of a
compound.
[0072] As used herein and unless otherwise indicated, the term
"enantiomerically pure" means a stereomerically pure composition of
a compound having one chiral center. Similarly, the term
"enantiomerically enriched" means a stereomerically enriched
composition of a compound having one chiral center.
[0073] Certain compounds of the present invention can exist in
unsolvated forms as well as solvated forms, including hydrated
forms. In general, solvated forms are equivalent to unsolvated
forms. Certain compounds of the invention may exist in multiple
crystalline or amorphous forms. In general, all physical forms are
equivalent for the uses contemplated by the present invention, and
are encompassed by the present invention.
[0074] Certain compounds of the present invention possess
asymmetric carbon atoms (optical or stereo-centers) or double
bonds; the racemates, enantiomers, diastereomers, geometric isomers
and mixtures thereof are all intended to be encompassed by this
invention.
[0075] Compounds of the invention may also contain unnatural
proportions of atomic isotopes at one or more of the atoms that
constitute such compounds. For example, the compounds may be
radiolabeled with radioactive isotopes, such as for example tritium
(.sup.3H), iodine-125 (.sup.125I) or carbon-14 (.sup.14C).
Radiolabeled compounds are useful as therapeutic agents, e.g.,
cancer therapeutic agents, research reagents, e.g., assay reagents,
and diagnostic agents, e.g., in vivo imaging agents. All isotopic
variations of the compounds of the present invention, whether
radioactive or not, are intended to be encompassed within the scope
of the present invention.
[0076] It should be noted that if there is a discrepancy between a
depicted structure and a name given that structure, the depicted
structure is to be accorded more weight. In addition, if the
stereochemistry of a structure or a portion of a structure is not
indicated with, for example, bold or dashed lines, the structure or
portion of the structure is to be interpreted as encompassing all
stereoisomers of it.
4.2 Second Active Agents
[0077] Compounds of this invention can be combined with other
pharmacologically active compounds ("second active agents") in
methods and compositions of the invention. It is believed that
certain combinations work synergistically in the treatment of
particular types of cancer and certain diseases and conditions
associated with, or characterized by, undesired angiogenesis.
Compounds of this invention can also work to alleviate adverse
effects associated with certain second active agents, and some
second active agents can be used to alleviate adverse effects that
may be associated with compounds of this invention.
[0078] One or more second active ingredients or agents can be used
in the methods and compositions of the invention together with a
compound of the invention. Second active agents can be large
molecules (e.g., proteins) or small molecules (e.g., synthetic
inorganic, organometallic, or organic molecules).
[0079] Examples of large molecule active agents include, but are
not limited to, hematopoietic growth factors, cytokines, and
monoclonal and polyclonal antibodies. Specific examples of the
active agents are anti-CD40 monoclonal antibodies (such as, for
example, SGN-40); histone deacetylyase inhibitors (such as, for
example, SAHA and LAQ 824); heat-shock protein-90 inhibitors (such
as, for example, 17-AAG); insulin-like growth factor-1 receptor
kinase inhibitors; vascular endothelial growth factor receptor
kinase inhibitors (such as, for example, PTK787); insulin growth
factor receptor inhibitors; lysophosphatidic acid acyltransrerase
inhibitors; IkB kinase inhibitors; p38MAPK inhibitors; EGFR
inhibitors (such as, for example, gefitinib and erlotinib HCL);
HER-2 antibodies (such as, for example, trastuzumab
(Herceptin.RTM.) and pertuzumab (Omnitarg.TM.)); VEGFR antibodies
(such as, for example, bevacizumab (Avastin.TM.)); VEGFR inhibitors
(such as, for example, flk-1 specific kinase inhibitors, SU5416 and
ptk787/zk222584); P13K inhibitors (such as, for example,
wortmannin); C-Met inhibitors (such as, for example, PHA-665752);
monoclonal antibodies (such as, for example, rituximab
(Rituxan.RTM.), tositumomab (Bexxar.RTM.), edrecolomab
(Panorex.RTM.) and G250); and anti-TNF-.alpha. antibodies.
[0080] Typical large molecule active agents are biological
molecules, such as naturally occurring or artificially made
proteins. Proteins that are particularly useful in this invention
include proteins that stimulate the survival and/or proliferation
of hematopoietic precursor cells and immunologically active poietic
cells in vitro or in vivo. Others stimulate the division and
differentiation of committed erythroid progenitors in cells in
vitro or in vivo. Particular proteins include, but are not limited
to: interleukins, such as IL-2 (including recombinant IL-II
("rIL2") and canarypox IL-2), IL-10, IL-12, and IL-18; interferons,
such as interferon alfa-2a, interferon alfa-2b, interferon alfa-n1,
interferon alfa-n3, interferon beta-I a, and interferon gamma-I b;
GM-CF and GM-CSF; and EPO.
[0081] Particular proteins that can be used in the methods and
compositions of the invention include, but are not limited to:
filgrastim, which is sold in the United States under the trade name
Neupogen.RTM. (Amgen, Thousand Oaks, Calif.); sargramostim, which
is sold in the United States under the trade name Leukine.RTM.
(Immunex, Seattle, Wash.); and recombinant EPO, which is sold in
the United States under the trade name Epogen.RTM. (Amgen, Thousand
Oaks, Calif.).
[0082] Recombinant and mutated forms of GM-CSF can be prepared as
described in U.S. Pat. Nos. 5,391,485; 5,393,870; and 5,229,496;
all of which are incorporated herein by reference. Recombinant and
mutated forms of G-CSF can be prepared as described in U.S. Pat.
Nos. 4,810,643; 4,999,291; 5,528,823; and 5,580,755; all of which
are incorporated herein by reference.
[0083] This invention encompasses the use of native, naturally
occurring, and recombinant proteins. The invention further
encompasses mutants and derivatives (e.g., modified forms) of
naturally occurring proteins that exhibit, in vivo, at least some
of the pharmacological activity of the proteins upon which they are
based. Examples of mutants include, but are not limited to,
proteins that have one or more amino acid residues that differ from
the corresponding residues in the naturally occurring forms of the
proteins. Also encompassed by the term "mutants" are proteins that
lack carbohydrate moieties normally present in their naturally
occurring forms (e.g., nonglycosylated forms). Examples of
derivatives include, but are not limited to, pegylated derivatives
and fusion proteins, such as proteins formed by fusing IgG1 or IgG3
to the protein or active portion of the protein of interest. See,
e.g., Penichet, M. L. and Morrison, S. L., J. Immunol. Methods
248:91-101 (2001).
[0084] Large molecule active agents may be administered in the form
of anti-cancer vaccines. For example, vaccines that secrete, or
cause the secretion of, cytokines such as IL-2, G-CSF, and GM-CSF
can be used in the methods, pharmaceutical compositions, and kits
of the invention. See, e.g., Emens, L. A., et al., Curr. Opinion
Mol. Ther. 3(1):77-84 (2001).
[0085] In one embodiment of the invention, the large molecule
active agent reduces, eliminates, or prevents an adverse effect
associated with the administration of a compound of this invention.
Depending on the particular compound and the disease or disorder
being treated, adverse effects may include, but are not limited to,
drowsiness and somnolence, dizziness and orthostatic hypotension,
neutropenia, infections that result from neutropenia, increased
HIV-viral load, bradycardia, Stevens-Johnson Syndrome and toxic
epidermal necrolysis, and seizures (e.g., grand mal convulsions). A
specific adverse effect is neutropenia.
[0086] Second active agents that are small molecules can also be
used to alleviate adverse effects associated with the
administration of a compound of this invention. However, like some
large molecules, many are believed to be capable of providing a
synergistic effect when administered with (e.g., before, after or
simultaneously) a compound of the invention. Examples of small
molecule second active agents include, but are not limited to,
anti-cancer agents, antibiotics, immunosuppressive agents, and
steroids.
[0087] Examples of anti-cancer agents include, but are not limited
to: semaxanib; cyclosporin; etanercept; doxycycline; bortezomib;
acivicin; aclarubicin; acodazole hydrochloride; acronine;
adozelesin; aldesleukin; altretamine; ambomycin; ametantrone
acetate; amsacrine; anastrozole; anthramycin; asparaginase;
asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;
bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;
bizelesin; bleomycin sulfate; brequinar sodium; bropirimine;
busulfan; cactinomycin; calusterone; caracemide; carbetimer;
carboplatin; carmustine; carubicin hydrochloride; carzelesin;
cedefingol; celecoxib (COX-2 inhibitor); chlorambucil; cirolemycin;
cisplatin; cladribine; crisnatol mesylate; cyclophosphamide;
cytarabine; dacarbazine; dactinomycin; daunorubicin hydrochloride;
decitabine; dexormaplatin; dezaguanine; dezaguanine mesylate;
diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;
droloxifene; droloxifene citrate; dromostanolone propionate;
duazomycin; edatrexate; eflomithine hydrochloride; elsamitrucin;
enloplatin; enpromate; epipropidine; epirubicin hydrochloride;
erbulozole; esorubicin hydrochloride; estramustine; estramustine
phosphate sodium; etanidazole; etoposide; etoposide phosphate;
etoprine; fadrozole hydrochloride; fazarabine; fenretinide;
floxuridine; fludarabine phosphate; fluorouracil; fluorocitabine;
fosquidone; fostriecin sodium; gemcitabine; gemcitabine
hydrochloride; hydroxyurea; idarubicin hydrochloride; ifosfamide;
ilmofosine; iproplatin; irinotecan; irinotecan hydrochloride;
lanreotide acetate; letrozole; leuprolide acetate; liarozole
hydrochloride; lometrexol sodium; lomustine; losoxantrone
hydrochloride; masoprocol; maytansine; mechlorethamine
hydrochloride; megestrol acetate; melengestrol acetate; melphalan;
menogaril; mercaptopurine; methotrexate; methotrexate sodium;
metoprine; meturedepa; mitindomide; mitocarcin; mitocromin;
mitogillin; mitomalcin; mitomycin; mitosper; mitotane; mitoxantrone
hydrochloride; mycophenolic acid; nocodazole; nogalamycin;
ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;
pentamustine; peplomycin sulfate; perfosfamide; pipobroman;
piposulfan; piroxantrone hydrochloride; plicamycin; plomestane;
porfimer sodium; porfiromycin; prednimustine; procarbazine
hydrochloride; puromycin; puromycin hydrochloride; pyrazofurin;
riboprine; safingol; safingol hydrochloride; semustine; simtrazene;
sparfosate sodium; sparsomycin; spirogermanium hydrochloride;
spiromustine; spiroplatin; streptonigrin; streptozocin; sulofenur;
talisomycin; tecogalan sodium; taxotere; tegafur; teloxantrone
hydrochloride; temoporfin; teniposide; teroxirone; testolactone;
thiamiprine; thioguanine; thiotepa; tiazofurin; tirapazamine;
toremifene citrate; trestolone acetate; triciribine phosphate;
trimetrexate; trimetrexate glucuronate; triptorelin; tubulozole
hydrochloride; uracil mustard; uredepa; vapreotide; verteporfin;
vinblastine sulfate; vincristine sulfate; vindesine; vindesine
sulfate; vinepidine sulfate; vinglycinate sulfate; vinleurosine
sulfate; vinorelbine tartrate; vinrosidine sulfate; vinzolidine
sulfate; vorozole; zeniplatin; zinostatin; and zorubicin
hydrochloride.
[0088] Other anti-cancer drugs include, but are not limited to:
20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;
aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin;
ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine;
aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;
andrographolide; angiogenesis inhibitors; antagonist D; antagonist
G; antarelix; anti-dorsalizing morphogenetic protein-1;
antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston;
antisense oligonucleotides; aphidicolin glycinate; apoptosis gene
modulators; apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA;
arginine deaminase; asulacrine; atamestane; atrimustine;
axinastatin 1; axinastatin 2; axinastatin 3; azasetron; azatoxin;
azatyrosine; baccatin III derivatives; balanol; batimastat; BCR/ABL
antagonists; benzochlorins; benzoylstaurosporine; beta lactam
derivatives; beta-alethine; betaclamycin B; betulinic acid; bFGF
inhibitor; bicalutamide; bisantrene; bisaziridinyispermine;
bisnafide; bistratene A; bizelesin; breflate; bropirimine;
budotitane; buthionine sulfoximine; calcipotriol; calphostin C;
camptothecin derivatives; capecitabine; carboxamide-amino-triazole;
carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived
inhibitor; carzelesin; casein kinase inhibitors (ICOS);
castanospermine; cecropin B; cetrorelix; chlorlns;
chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin;
cladribine; clomifene analogues; clotrimazole; collismycin A;
collismycin B; combretastatin A4; combretastatin analogue;
conagenin; crambescidin 816; crisnatol; cryptophycin 8;
cryptophycin A derivatives; curacin A; cyclopentanthraquinones;
cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;
cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;
dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;
diaziquone; didemnin B; didox; diethylnorspermine;
dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenyl
spiromustine; docetaxel; docosanol; dolasetron; doxifluridine;
doxorubicin; droloxifene; dronabinol; duocarmycin SA; ebselen;
ecomustine; edelfosine; edrecolomab; eflomithine; elemene;
emitefur; epirubicin; epristeride; estramustine analogue; estrogen
agonists; estrogen antagonists; etanidazole; etoposide phosphate;
exemestane; fadrozole; fazarabine; fenretinide; filgrastim;
finasteride; flavopiridol; flezelastine; fluasterone; fludarabine;
fluorodaunorunicin hydrochloride; forfenimex; formestane;
fostriecin; fotemustine; gadolinium texaphyrin; gallium nitrate;
galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;
glutathione inhibitors; hepsulfam; heregulin; hexamethylene
bisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;
idramantone; ilmofosine; ilomastat; imatinib (e.g., Gleevec.RTM.),
imiquimod; immunostimulant peptides; insulin-like growth factor-1
receptor inhibitor; interferon agonists; interferons; interleukins;
iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine;
isobengazole; isohomohalicondrin B; itasetron; jasplakinolide;
kahalalide F; lamellarin-N triacetate; lanreotide; leinamycin;
lenograstim; lentinan sulfate; leptolstatin; letrozole; leukemia
inhibiting factor; leukocyte alpha interferon;
leuprolide+estrogen+progesterone; leuprorelin; levamisole;
liarozole; linear polyamine analogue; lipophilic disaccharide
peptide; lipophilic platinum compounds; lissoclinamide 7;
lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;
loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lytic
peptides; maitansine; mannostatin A; marimastat; masoprocol;
maspin; matrilysin inhibitors; matrix metalloproteinase inhibitors;
menogaril; merbarone; meterelin; methioninase; metoclopramide; MIF
inhibitor; mifepristone; miltefosine; mirimostim; mitoguazone;
mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast
growth factor-saporin; mitoxantrone; mofarotene; molgramostim;
Erbitux, human chorionic gonadotrophin; monophosphoryl lipid
A+myobacterium cell wall sk; mopidamol; mustard anticancer agent;
mycaperoxide B; mycobacterial cell wall extract; myriaporone;
N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;
naloxone+pentazocine; napavin; naphterpin; nartograstim;
nedaplatin; nemorubicin; neridronic acid; nilutamide; nisamycin;
nitric oxide modulators; nitroxide antioxidant; nitrullyn;
oblimersen (Genasense.RTM.); O.sup.6-benzylguanine; octreotide;
okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;
oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;
oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel
derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;
panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;
peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;
perflubron; perfosfamide; perillyl alcohol; phenazinomycin;
phenylacetate; phosphatase inhibitors; picibanil; pilocarpine
hydrochloride; pirarubicin; piritrexim; placetin A; placetin B;
plasminogen activator inhibitor; platinum complex; platinum
compounds; platinum-triamine complex; porfimer sodium;
porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;
proteasome inhibitors; protein A-based immune modulator; protein
kinase C inhibitor; protein kinase C inhibitors, microalgal;
protein tyrosine phosphatase inhibitors; purine nucleoside
phosphorylase inhibitors; purpurins; pyrazoloacridine;
pyridoxylated hemoglobin polyoxyethylene conjugate; raf
antagonists; raltitrexed; ramosetron; ras farnesyl protein
transferase inhibitors; ras inhibitors; ras-GAP inhibitor;
retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;
ribozymes; RII retinamide; rohitukine; romurtide; roquinimex;
rubiginone B1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A;
sargramostim; Sdi 1 mimetics; semustine; senescence derived
inhibitor 1; sense oligonucleotides; signal transduction
inhibitors; sizofuran; sobuzoxane; sodium borocaptate; sodium
phenylacetate; solverol; somatomedin binding protein; sonermin;
sparfosic acid; spicamycin D; spiromustine; splenopentin;
spongistatin 1; squalamine; stipiamide; stromelysin inhibitors;
sulfinosine; superactive vasoactive intestinal peptide antagonist;
suradista; suramin; swainsonine; tallimustine; tamoxifen
methiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;
tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;
tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;
thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietin
receptor agonist, thymotrinan; thyroid stimulating hormone; tin
ethyl etiopurpurin; tirapazamine; titanocene bichloride; topsentin;
toremifene; translation inhibitors; tretinoin; triacetyluridine;
triciribine; trimetrexate; triptorelin; tropisetron; turosteride;
tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;
urogenital sinus-derived growth inhibitory factor; urokinase
receptor antagonists; vapreotide; variolin B; velaresol; veramine;
verdins; verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole;
zanoterone; zeniplatin; zilascorb; and zinostatin stimalamer.
[0089] Specific second active agents include, but are not limited
to, 2-methoxyestradiol, telomestatin, inducers of apoptosis in
multiple myeloma cells (such as, for example, TRAIL), statins,
semaxanib, cyclosporin, etanercept, doxycycline, bortezomib,
oblimersen (Genasense.RTM.), remicade, docetaxel, celecoxib,
melphalan, dexamethasone (Decadron.RTM.), steroids, gemcitabine,
cisplatinum, temozolomide, etoposide, cyclophosphamide, temodar,
carboplatin, procarbazine, gliadel, tamoxifen, topotecan,
methotrexate, Arisa.RTM., taxol, taxotere, fluorouracil,
leucovorin, irinotecan, xeloda, CPT-11, interferon alpha, pegylated
interferon alpha (e.g., PEG INTRON-A), capecitabine, cisplatin,
thiotepa, fludarabine, carboplatin, liposomal daunorubicin,
cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,
dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,
busulphan, prednisone, bisphosphonate, arsenic trioxide,
vincristine, doxorubicin (Doxil.RTM.), paclitaxel, ganciclovir,
adriamycin, estramustine sodium phosphate (Emcyt.RTM.), sulindac,
and etoposide.
4.3 Methods of Treatments and Prevention
[0090] Methods of this invention encompass methods of treating,
preventing and/or managing various types of cancer, diseases and
disorders associated with, or characterized by, undesired
angiogenesis, and diseases and disorders mediated by PDE 4, which
comprise administering to a patient in need of such treatment,
prevention and/or management an effective amount of a compound of
this invention. As used herein, unless otherwise specified, the
term "treating" refers to the administration of a compound of the
invention or other additional active agent after the onset of
symptoms of the particular disease or disorder. As used herein,
unless otherwise specified, the term "preventing" refers to the
administration prior to the onset of symptoms, particularly to
patients at risk of cancer, and other diseases and disorders
associated with, or characterized by, undesired angiogenesis. The
term "prevention" includes the inhibition of a symptom of the
particular disease or disorder. Patients with familial history of
cancer and diseases and disorders associated with, or characterized
by, undesired angiogenesis are preferred candidates for preventive
regimens. As used herein and unless otherwise indicated, the term
"managing" encompasses preventing the recurrence of the particular
disease or disorder in a patient who had suffered from it, and/or
lengthening the time a patient who had suffered from the disease or
disorder remains in remission.
[0091] As used herein, and unless otherwise specified, the term
"effective amount" refers to the amount of the compound being
administered sufficient to prevent development of or alleviate to
some extent one or more of the symptoms of the condition or
disorder being treated as well as to alleviate or eradicate the
cause of the disease itself.
[0092] As used herein, the term "cancer" includes, but is not
limited to, solid tumors and blood born tumors. The term "cancer"
refers to disease of skin tissues, organs, blood, and vessels,
including, but not limited to, cancers of the bladder, bone or
blood, brain, breast, cervix, chest, colon, endrometrium,
esophagus, eye, head, kidney, liver, lymph nodes, lung, mouth,
neck, ovaries, pancreas, prostate, rectum, stomach, testis, throat,
and uterus. The cancer can be primary or metastatic. Specific
cancers include, but are not limited to, advanced malignancy,
amyloidosis, neuroblastoma, meningioma, atypical meningioma,
hemangiopericytoma, multiple brain metastase, glioblastoma
multiforms, glioblastoma, brain stem glioma, poor prognosis
malignant brain tumor, malignant glioma, recurrent malignant
glioma, anaplastic astrocytoma, anaplastic oligodendroglioma,
neuroendocrine tumor, rectal adenocarcinoma, Dukes C & D
colorectal cancer, unresectable colorectal carcinoma, metastatic
hepatocellular carcinoma, Kaposi's sarcoma, karotype acute
myeloblastic leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma,
cutaneous T-Cell lymphoma, cutaneous B-Cell lymphoma, diffuse large
B-Cell lymphoma, low grade follicular lymphoma, melanoma,
including, but not limited to, metastatic melanoma (localized
melanoma, including ocular melanoma), malignant mesothelioma,
malignant pleural effusion mesothelioma syndrome, peritoneal
carcinoma, papillary serous carcinoma, gynecologic sarcoma, soft
tissue sarcoma, scelroderma, cutaneous vasculitis, Langerhans cell
histiocytosis, leiomyosarcoma, fibrodysplasia ossificans
progressive, hormone refractory prostate cancer, resected high-risk
soft tissue sarcoma, unrescectable hepatocellular carcinoma,
Waldenstrom's macroglobulinemia, myeloma including, but not limited
to, multiple myeloma, smoldering myeloma and indolent myeloma,
fallopian tube cancer, androgen independent prostate cancer,
androgen dependent stage IV non-metastatic prostate cancer,
hormone-insensitive prostate cancer, chemotherapy-insensitive
prostate cancer, carcinoma including, but not limited to, papillary
thyroid carcinoma, follicular thyroid carcinoma, and medullary
thyroid carcinoma, and leiomyoma. In a specific embodiment, the
cancer is metastatic. In another embodiment, the cancer is
refractory or resistance to chemotherapy or radiation; in
particular, refractory to thalidomide.
[0093] As used herein, and unless otherwise specified, the terms
"diseases or disorders associated with, or characterized by,
undesired angiogenesis," "diseases or disorders associated with
undesired angiogenesis," and "diseases or disorders characterized
by undesired angiogenesis" refer to diseases, disorders and
conditions that are caused, mediated or attended by undesired,
unwanted or uncontrolled angiogenesis, including, but not limited
to, inflammatory diseases, autoimmune diseases, genetic diseases,
allergic diseases, bacterial diseases, ocular neovascular diseases,
choroidal neovascular diseases, and retina neovascular
diseases.
[0094] Examples of such diseases or disorders associated with
undesired angiogenesis include, but are not limited to,
endometriosis, Crohn's disease, heart failure, advanced heart
failure, renal impairment, diabetic retinopathy, retinopathy of
prematurity, corneal graft rejection, neovascular glaucoma,
retrolental fibroplasia, proliferative vitreoretinopathy, trachoma,
myopia, optic pits, epidemic keratoconjunctivitis; atopic
keratitis, superior limbic keratitis, pterygium keratitis sicca,
sjogrens, acne rosacea, phylectenulosis, syphilis, lipid
degeneration, bacterial ulcer, fungal ulcer, Herpes simplex
infection, Herpes zoster infection, protozoan infection, Kaposi
sarcoma, Mooren ulcer, Terrien's marginal degeneration, mariginal
keratolysis, myelodysplastic syndrome, rheumatoid arthritis,
systemic lupus, polyarteritis, trauma, Wegeners sarcoidosis,
scleritis, Steven's Johnson disease, periphigoid radial keratotomy,
sickle cell anemia, sarcoid, pseudoxanthoma elasticum, Pagets
disease, vein occlusion, artery occlusion, carotid obstructive
disease, chronic uveitis, chronic vitritis, Lyme's disease, Eales
disease, Bechet's disease, retinitis, choroiditis, presumed ocular
histoplasmosis, Bests disease, Stargarts disease, pars planitis,
chronic retinal detachment, hyperviscosity syndromes,
toxoplasmosis, rubeosis, sarcodisis, sclerosis, soriatis,
psoriasis, primary sclerosing cholangitis, proctitis, primary
biliary srosis, idiopathic pulmonary fibrosis, alcoholic hepatitis,
endotoxemia, toxic shock syndrome, osteoarthritis, retrovirus
replication, wasting, meningitis, silica-induced fibrosis,
asbestos-induced fibrosis, malignancy-associated hypercalcemia,
stroke, circulatory shock, periodontitis, gingivitis, macrocytic
anemia, refractory anemia, 5q-syndrome, and veterinary disorder
caused by feline immunodeficiency virus, equine infectious anemia
virus, caprine arthritis virus, visna virus, maedi virus or lenti
virus.
[0095] In specific embodiments of the invention, diseases or
disorders associated with undesired angiogenesis do not include
congestive heart failure, cardiomyopathy, pulmonary edema,
endotoxin-mediated septic shock, acute viral myocarditis, cardiac
allograft rejection, myocardial infarction, HIV, hepatitis, adult
respiratory distress syndrome, bone-resorption disease, chronic
obstructive pulmonary diseases, chronic pulmonary inflammatory
disease, dermatitis, cystic fibrosis, septic shock, sepsis,
endotoxic shock, hemodynamic shock, sepsis syndrome, post ischemic
reperfusion injury, fibrotic disease, cachexia, graft rejection,
rheumatoid spondylitis, osteoporosis, ulcerative colitis,
inflammatory-bowel disease, multiple sclerosis, systemic lupus
erythrematosus, erythema nodosum leprosum in leprosy, radiation
damage, asthma, hyperoxic alveolar injury, malaria, mycobacterial
infection, and opportunistic infections resulting from HIV.
[0096] As used herein, and unless otherwise specified, the term
"diseases or disorders mediated by PDE 4" means a condition or
disorder that responds favorably to modulation, for example,
reduction (e.g., inhibition), of PDE 4 activity. Favorable
responses to PDE 4 modulation include alleviation or abrogation of
the disease and/or its attendant symptoms, inhibition of the
disease (i.e., arrest or reduction of the development of the
disease), or its clinical symptoms, and regression of the disease
or its clinical symptoms. A disease or disorder mediated by PDE 4
may be completely or partially responsive to PDE 4 modulation. A
disease or disorder mediated by PDE 4 may be associated with
inappropriate, e.g., less than or greater than normal, PDE 4
activity. Inappropriate PDE 4 functional activity might arise as
the result of PDE 4 expression in cells which normally do not
express PDE 4, decreased PDE 4 expression (leading to, e.g., lipid
and metabolic disorders and diseases) or increased PDE 4
expression.
[0097] As used herein, and unless otherwise specified, the terms
"modulate" and "modulation" means that the activity or expression
of the molecule (e.g., an enzyme) to be modulated is enhanced or
decreased. In some embodiments, the activity or expression of the
molecule to be modulated is enhanced by 10%, 20%, 50%, 100%, or
200% or more, as compared to the activity or expression of the
molecule without the modulation. In other embodiments, the activity
or expression of the molecule to be modulated is decreased by 10%,
20%, 50%, 70%, 80%, or 90% or more, as compared to the activity or
expression of the molecule without the modulation.
[0098] Examples of diseases or disorders mediated by PDE 4 include,
but are not limited to, asthma, atopic dermatitis, depression,
reperfusion injury, septic shock, toxic shock, endotoxic shock,
adult respiratory distress syndrome, autoimmune diabetes, diabetes
insipidus, multi-infarct dementia, AIDS, cancer, Crohn's disease,
multiple sclerosis, cerebral ischemia, psoriasis, allograft
rejection, restenosis, ulceratiave colitis, cachexia, cerebral
malaria, allergic rhino-conjunctivitis, osteoarthritis, rheumatoid
arthritis, chronic obstructive pulmonary disease (COPD), chronic
bronchitis, cosinophilic granuloma, and autoimmune
encephalomyelitis.
[0099] This invention encompasses methods of treating patients who
have been previously treated for cancer, diseases or disorders
associated with, or characterized by, undesired angiogenesis, or
diseases or disorders mediated by PDE 4, but are non-responsive to
standard therapies, as well as those who have not previously been
treated. The invention also encompasses methods of treating
patients regardless of patient's age, although some diseases or
disorders are more common in certain age groups. The invention
further encompasses methods of treating patients who have undergone
surgery in an attempt to treat the disease or condition at issue,
as well as those who have not. Because patients with cancer and
diseases and disorders characterized by undesired angiogenesis or
mediated by PDE 4 have heterogenous clinical manifestations and
varying clinical outcomes, the treatment given to a patient may
vary, depending on his/her prognosis. The skilled clinician will be
able to readily determine without undue experimentation specific
secondary agents, types of surgery, and types of non-drug based
standard therapy that can be effectively used to treat an
individual patient with cancer and other diseases or disorders.
[0100] Methods encompassed by this invention comprise administering
one or more compounds of the invention to a patient (e.g., a human)
who is suffering, or likely to suffer, from cancer, a disease or
disorder mediated by undesired angiogenesis, or a disease or
disorder mediated by PDE 4.
[0101] In one embodiment of the invention, the recommended daily
dose range of a compound of this invention for the conditions
described herein lie within the range of from about 1 mg to about
10,000 mg per day, given as a single once-a-day dose, or preferably
in divided doses throughout a day. More specifically, the daily
dose is administered twice daily in equally divided doses.
Specifically, a daily dose range should be from about 1 mg to about
5,000 mg per day, more specifically, between about 10 mg and about
2,500 mg per day, between about 100 mg and about 800 mg per day,
between about 100 mg and about 1,200 mg per day, or between about
25 mg and about 2,500 mg per day. In managing the patient, the
therapy should be initiated at a lower dose, perhaps about 1 mg to
about 2,500 mg, and increased if necessary up to about 200 mg to
about 5,000 mg per day as either a single dose or divided doses,
depending on the patient's global response.
4.3.1 Combination Therapy with a Second Active Agent
[0102] Specific methods of the invention comprise administering a
compound of this invention, or a pharmaceutically acceptable salt,
solvate, hydrate, stereoisomer, clathrate, or prodrug thereof, in
combination with one or more second active agents, and/or in
combination with radiation therapy, blood transfusions, or surgery.
Examples of second active agents are also disclosed herein (see,
e.g., section 4.2).
[0103] Administration of the compound of this invention and the
second active agents to a patient can occur simultaneously or
sequentially by the same or different routes of administration. The
suitability of a particular route of administration employed for a
particular active agent will depend on the active agent itself
(e.g., whether it can be administered orally without decomposing
prior to entering the blood stream) and the disease being treated.
A preferred route of administration for a compound of this
invention of the invention is oral or ophthalmic. Preferred routes
of administration for the second active agents or ingredients of
the invention are known to those of ordinary skill in the art. See,
e.g., Physicians'Desk Reference, 1755-1760 (56.sup.th ed.,
2002).
[0104] In one embodiment of the invention, the second active agent
is administered intravenously or subcutaneously and once or twice
daily in an amount of from about 1 to about 1000 mg, from about 5
to about 500 mg, from about 10 to about 350 mg, or from about 50 to
about 200 mg. The specific amount of the second active agent will
depend on the specific agent used, the type of disease being
treated or managed, the severity and stage of disease, and the
amount(s) of compounds of the invention and any optional additional
active agents concurrently administered to the patient. In a
particular embodiment, the second active agent is oblimersen
(Genasense.RTM.), GM-CSF, G-CSF, EPO, taxotere, irinotecan,
dacarbazine, transretinoic acid, topotecan, pentoxifylline,
ciprofloxacin, dexamethasone, vincristine, doxorubicin, cox-2
inhibitors, IL2, IL8, IL18, IFN, Ara-C, vinorelbine, or a
combination thereof.
[0105] In a particular embodiment, GM-CSF, G-CSF or EPO is
administered subcutaneously during about five days in a four or six
week cycle in an amount of from about 1 to about 750
mg/m.sup.2/day, preferably in an amount of from about 25 to about
500 mg/m.sup.2/day, more preferably in an amount of from about 50
to about 250 mg/m.sup.2/day, and most preferably in an amount of
from about 50 to about 200 mg/m.sup.2/day. In a certain embodiment,
GM-CSF may be administered in an amount of from about 60 to about
500 mcg/m.sup.2 intravenously over 2 hours, or from about 5 to
about 12 mcg/m.sup.2/day subcutaneously. In a specific embodiment,
G-CSF may be administered subcutaneously in an amount of about 1
mcg/kg/day initially and can be adjusted depending on rise of total
granulocyte counts. The maintenance dose of G-CSF may be
administered in an amount of about 300 (in smaller patients) or 480
mcg subcutaneously. In a certain embodiment, EPO may be
administered subcutaneously in an amount of 10,000 Unit 3 times per
week.
[0106] In another embodiment, a compound of this invention is
administered in an amount of from about 20 mg to about 1,200 mg/d
alone or in combination with a second active agent to patients with
metastatic melanoma (localized melanoma, including, but not limited
to, ocular melanoma). In one embodiment, a compound of this
invention in an amount of from about 800 to about 1,200 mg/d and
dacarbazine (DTIC) in an amount of from about 200 to about 1000
mg/m.sup.2/d are administered to patients with metastatic melanoma
(localized melanoma, including, but not limited to, ocular
melanoma). In another embodiment, a compound of this invention in
an amount of about from 800 to 1,200 mg/d and temozolomide are
administered to patients with metastatic melanoma (localized
melanoma, including, but not limited to, ocular-melanoma). In
another embodiment, a compound of this invention is administered to
patients with metastatic melanoma or localized melanoma whose
disease has progressed on treatment with temozolomide, dacarbazine
(DTIC), IL-2 and/or IFN. In a specific embodiment, a compound of
this invention is administered to patients with relapsed or
refractory multiple myeloma in combination with dexamethasone.
[0107] In another embodiment, a compound of this invention is
administered with melphalan and dexamethasone to patients with
amyloidosis. In a specific embodiment, a compound of the invention
and steroids can be administered to patients with amyloidosis.
[0108] In another embodiment, a compound of this invention is
administered with gemcitabine and cisplatinum to patients with
locally advanced or metastatic transitional cell bladder
cancer.
[0109] In another embodiment, a compound of this invention is
administered in combination with a second active ingredient as
follows: temozolomide to pediatric patients with relapsed or
progressive brain tumors or recurrent neuroblastoma; celecoxib,
etoposide and cyclophosphamide for relapsed or progressive CNS
cancer; temodar to patients with recurrent or progressive
meningioma, malignant meningioma, hemangiopericytoma, multiple
brain metastases, relapased brain tumors, or newly diagnosed
glioblastoma multiforms; irinotecan to patients with recurrent
glioblastoma; carboplatin to pediatric patients with brain stem
glioma; procarbazine to pediatric patients with progressive
malignant gliomas; cyclophosphamide to patients with poor prognosis
malignant brain tumors, newly diagnosed or recurrent glioblastoma
multiforms; Gliadel.RTM. for high grade recurrent malignant
gliomas; temozolomide and tamoxifen for anaplastic astrocytoma; or
topotecan for gliomas, glioblastoma, anaplastic astrocytoma or
anaplastic oligodendroglioma.
[0110] In another embodiment, a compound of this invention is
administered with methotrexate and cyclophosphamide to patients
with metastatic breast cancer.
[0111] In another embodiment, a compound of this invention is
administered with temozolomide to patients with neuroendocrine
tumors.
[0112] In another embodiment, a compound of this invention is
administered with gemcitabine to patients with recurrent or
metastatic head or neck cancer. In another embodiment, a compound
of this invention is administered with gemcitabine to patients with
pancreatic cancer.
[0113] In another embodiment, a compound of this invention is
administered to patients with colon cancer in combination with
Arisa.RTM., taxol and/or taxotere.
[0114] In another embodiment, a compound of this invention is
administered with capecitabine to patients with refractory
colorectal cancer or patients who fail first line therapy or have
poor performance in colon or rectal adenocarcinoma.
[0115] In another embodiment, a compound of this invention is
administered in combination with fluorouracil, leucovorin, and
irinotecan to patients with Dukes C & D colorectal cancer or to
patients who have been previously treated for metastatic colorectal
cancer.
[0116] In another embodiment, a compound of this invention is
administered to patients with refractory colorectal cancer in
combination with capecitabine, xeloda, and/or CPT-11.
[0117] In another embodiment, a compound of the invention is
administered with capecitabine and irinotecan to patients with
refractory colorectal cancer or to patients with unresectable or
metastatic colorectal carcinoma.
[0118] In another embodiment, a compound of this invention is
administered alone or in combination with interferon alpha or
capecitabine to patients with unresectable or metastatic
hepatocellular carcinoma; or with cisplatin and thiotepa to
patients with primary or metastatic liver cancer.
[0119] In another embodiment, a compound of this invention is
administered in combination with pegylated interferon alpha to
patients with Kaposi's sarcoma.
[0120] In another embodiment, a compound of this invention is
administered in combination with fludarabine, carboplatin, and/or
topotecan to patients with refractory or relapsed or high-risk
acuted myelogenous leukemia.
[0121] In another embodiment, a compound of this invention is
administered in combination with liposomal daunorubicin, topotecan
and/or cytarabine to patients with unfavorable karotype acute
myeloblastic leukemia.
[0122] In another embodiment, a compound of this invention is
administered in combination with gemcitabine and irinotecan to
patients with non-small cell lung cancer. In one embodiment, a
compound of this invention is administered in combination with
carboplatin and irinotecan to patients with non-small cell lung
cancer. In one embodiment, a compound of this invention is
administered with doxetaxol to patients with non-small cell lung
cancer who have been previously treated with carbo/VP 16 and
radiotherapy.
[0123] In another embodiment, a compound of this invention is
administered in combination with carboplatin and/or taxotere, or in
combination with carboplatin, pacilitaxel and/or thoracic
radiotherapy to patients with non-small cell lung cancer. In a
specific embodiment, a compound of this invention is administered
in combination with taxotere to patients with stage IIIB or IV
non-small cell lung cancer.
[0124] In another embodiment, a compound of this invention is
administered in combination with oblimersen (Genasense.RTM.) to
patients with small cell lung cancer.
[0125] In another embodiment, a compound of this invention is
administered alone or in combination with a second active
ingredient such as vinblastine or fludarabine to patients with
various types of lymphoma, including, but not limited to, Hodgkin's
lymphoma, non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma,
cutaneous B-Cell lymphoma, diffuse large B-Cell lymphoma or
relapsed or refractory low grade follicular lymphoma.
[0126] In another embodiment, a compound of this invention is
administered in combination with taxotere, IL-2, IFN, GM-CSF,
and/or dacarbazine to patients with various types or stages of
melanoma including, but not limited to, localized melanoma or
metastatic melanoma such as ocular melanoma.
[0127] In another embodiment, a compound of this invention is
administered alone or in combination with vinorelbine to patients
with malignant mesothelioma, or stage IIIB non-small cell lung
cancer with pleural implants or malignant pleural effusion
mesothelioma syndrome.
[0128] In another embodiment, a compound of this invention is
administered to patients with various types or stages of multiple
myeloma in combination with dexamethasone, zoledronic acid,
palmitronate, GM-CSF, biaxin, vinblastine, melphalan, busulphan,
cyclophosphamide, IFN, palmidronate, prednisone, bisphosphonate,
celecoxib, arsenic trioxide, PEG INTRON-A, vincristine, doxil,
decadron, or a combination thereof.
[0129] In another embodiment, a compound of this invention is
administered to patients with relapsed or refractory multiple
myeloma in combination with doxorubicin (Doxil.RTM.), vincristine
and/or dexamethasone (Decadron.RTM.).
[0130] In another embodiment, a compound of this invention is
administered to patients with various types or stages of ovarian
cancer such as peritoneal carcinoma, papillary serous carcinoma,
refractory ovarian cancer or recurrent ovarian cancer, in
combination with taxol, carboplatin, doxorubicin, gemcitabine,
cisplatin, xeloda, paclitaxel, dexamethasone, or a combination
thereof.
[0131] In another embodiment, a compound of this invention is
administered to patients with various types or stages of prostate
cancer, in combination with xeloda, 5 FU/LV, gemcitabine,
irinotecan plus gemcitabine, cyclophosphamide, vincristine,
dexamethasone, GM-CSF, celecoxib, taxotere, ganciclovir,
paclitaxel, adriamycin, docetaxel, estramustine, Emcyt, or a
combination thereof.
[0132] In another embodiment, a compound of this invention is
administered to patients with various types or stages of renal cell
cancer, in combination with capecitabine, IFN, tamoxifen, IL-2,
GM-CSF, Celebrex.RTM., or a combination thereof.
[0133] In another embodiment, a compound of this invention is
administered to patients with various types or stages of
gynecologic, uterus or soft tissue sarcoma cancer in combination
with IFN, a COX-2 inhibitor such as Celebrex.RTM., and/or
sulindac.
[0134] In another embodiment, a compound of this invention is
administered to patients with various types or stages of solid
tumors in combination with celebrex, etoposide, cyclophosphamide,
docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a
combination thereof.
[0135] In another embodiment, a compound of this invention is
administered to patients with scelroderma or cutaneous vasculitis
in combination with celebrex, etoposide, cyclophosphamide,
docetaxel, apecitabine, IFN, tamoxifen, IL-2, GM-CSF, or a
combination thereof.
[0136] This invention also encompasses a method of increasing the
dosage of an anti-cancer drug or agent that can be safely and
effectively administered to a patient, which comprises
administering to a patient (e.g., a human) a compound of this
invention. Patients that can benefit by this method are those
likely to suffer from an adverse effect associated with anti-cancer
drugs for treating a specific cancer of the skin, subcutaneous
tissue, lymph nodes, brain, lung, liver, bone, intestine, colon,
heart, pancreas, adrenal, kidney, prostate, breast, colorectal, or
combinations thereof. The administration of a compound of this
invention alleviates or reduces adverse effects which are of such
severity that it would otherwise limit the amount of anti-cancer
drug.
[0137] In one embodiment, a compound of this invention can be
administered orally and daily in an amount of from about 1 to about
5,000 mg, from about 10 to about 2,500 mg, from about 25 to about
2,500 mg, from about 100 to about 1,200 mg, or from about 100 to
about 800 mg prior to, during, or after the occurrence of the
adverse effect associated with the administration of an anti-cancer
drug to a patient. In a particular embodiment, a compound of this
invention is administered in combination with specific agents such
as heparin, aspirin, coumadin, or G-CSF to avoid adverse effects
that are associated with anti-cancer drugs such as but not limited
to neutropenia or thrombocytopenia.
[0138] In one embodiment, a compound of this invention can be
administered to patients with diseases and disorders associated
with, or characterized by, undesired angiogenesis, optionally in
combination with additional active ingredients including but not
limited to anti-cancer drugs, anti-inflammatories, antihistamines,
antibiotics, and steroids.
[0139] In another embodiment, this invention encompasses a method
of treating, preventing and/or managing cancer, which comprises
administering a compound of this invention, optionally in
conjunction with (e.g. before, during, or after) conventional
therapy including, but not limited to, surgery, immunotherapy,
biological therapy, radiation therapy, or other non-drug based
therapy presently used to treat, prevent or manage cancer. The
combined use of the compounds of this invention and conventional
therapy may provide a unique treatment regimen that is unexpectedly
effective in certain patients. Without being limited by theory, it
is believed that compound of this invention may provide additive or
synergistic effects when given concurrently with conventional
therapy.
[0140] In another embodiment, this invention encompasses a method
of treating, preventing and/or managing diseases and disorders
associated with, or characterized by, undesired angiogenesis, which
comprises administering a compound of this invention, optionally in
conjunction with (e.g. before, during, or after) conventional
therapy including, but not limited to, surgery, immunotherapy,
biological therapy, radiation therapy, or other non-drug based
therapy presently used to treat, prevent or manage diseases and
disorders associated with, or characterized by, undesired
angiogenesis. The combined use of the compounds of this invention
and conventional therapy may provide a unique treatment regimen
that is unexpectedly effective in certain patients. Without being
limited by theory, it is believed that the compounds of this
invention may provide additive or synergistic effects when given
concurrently with conventional therapy.
[0141] As discussed elsewhere herein, the invention encompasses a
method of reducing, treating and/or preventing adverse or undesired
effects associated with conventional therapy including, but not
limited to, surgery, chemotherapy, radiation therapy, hormonal
therapy, biological therapy and immunotherapy. One or more
compounds of this invention, optionally with other active
ingredient, can be administered to a patient prior to, during, or
after the occurrence of the adverse effect associated with
conventional therapy.
[0142] In one embodiment, a compound of this invention can be
administered in an amount of from about 1 to about 5,000 mg, from
about 10 to about 2,500 mg, from about 25 to about 2,500 mg, from
about 100 to about 1,200 mg, or from about 100 to about 800 mg
orally and daily alone, or in combination with a second active
agent disclosed herein (see, e.g., section 4.2), prior to, during,
or after the use of conventional therapy.
[0143] In a specific embodiment of this method, a compound of this
invention and doxetaxol are administered to patients with non-small
cell lung cancer who were previously treated with carbo/VP 16 and
radiotherapy.
4.3.2 Use with Transplantation Therapy
[0144] Compounds of the invention can be used to reduce the risk of
Graft Versus Host Disease (GVHD). Therefore, the invention
encompasses a method of treating, preventing and/or managing
cancer, which comprises administering a compound of this invention,
optionally in conjunction with transplantation therapy.
[0145] As those of ordinary skill in the art are aware, the
treatment of cancer is often based on the stages and mechanism of
the disease. For example, as inevitable leukemic transformation
develops in certain stages of cancer, transplantation of peripheral
blood stem cells, hematopoietic stem cell preparation or bone
marrow may be necessary. The combined use of the compound of this
invention and transplantation therapy provides a unique and
unexpected synergism. In particular, a compound of this invention
exhibits activity that may provide additive or synergistic effects
when given concurrently with transplantation therapy in patients
with cancer.
[0146] A compound of this invention can work in combination with
transplantation therapy reducing complications associated with the
invasive procedure of transplantation and risk of GVHD. This
invention encompasses a method of treating, preventing and/or
managing cancer which comprises administering to a patient (e.g., a
human) a compound of this invention, before, during, or after the
transplantation of umbilical cord blood, placental blood,
peripheral blood stem cell, hematopoietic stem cell preparation or
bone marrow. Examples of stem cells suitable for use in the methods
of the invention are disclosed in U.S. patent application Ser. No.
10/411,655, filed Apr. 11, 2003 by R. Hariri et al., the entirety
of which is incorporated herein by reference.
[0147] In another embodiment, this invention encompasses a method
of treating, preventing and/or managing diseases and disorders
associated with, or characterized by, undesired angiogenesis, which
comprises administering to a patient (e.g., a human) a compound of
this invention, before, during, or after the transplantation of
umbilical cord blood, placental blood, peripheral blood stem cell,
hematopoietic stem cell preparation or bone marrow.
[0148] In one embodiment of this method, a compound of this
invention is administered to patients with multiple myeloma before,
during, or after the transplantation of autologous peripheral blood
progenitor cell.
[0149] In another embodiment, a compound of this invention is
administered to patients with relapsing multiple myeloma after the
stem cell transplantation.
[0150] In another embodiment, a compound of this invention and
prednisone are administered as maintenance therapy to patients with
multiple myeloma following the transplantation of autologous stem
cell.
[0151] In another embodiment, a compound of this invention and
dexamethasone are administered as salvage therapy for low risk post
transplantation to patients with multiple myeloma.
[0152] In another embodiment, a compound of this invention and
dexamethasone are administered as maintenance therapy to patients
with multiple myeloma following the transplantation of autologous
bone marrow.
[0153] In another embodiment, a compound of this invention is
administered following the administration of high dose of melphalan
and the transplantation of autologous stem cell to patients with
chemotherapy responsive multiple myeloma.
[0154] In another embodiment, a compound of this invention and PEG
INTRO-A are administered as maintenance therapy to patients with
multiple myeloma following the transplantation of autologous
CD34-selected peripheral stem cell.
[0155] In another embodiment, a compound of this invention is
administered with post transplant consolidation chemotherapy to
patients with newly diagnosed multiple myeloma to evaluate
anti-angiogenesis.
[0156] In another embodiment, a compound of this invention and
dexamethasone are administered as maintenance therapy after DCEP
consolidation, following the treatment with high dose of melphalan
and the transplantation of peripheral blood stem cell to 65 years
of age or older patients with multiple myeloma.
4.3.3 Cycling Therapy
[0157] In certain embodiments, the prophylactic or therapeutic
agents of the invention are cyclically administered to a patient.
Cycling therapy involves the administration of an active agent for
a period of time, followed by a rest for a period of time, and
repeating this sequential administration. Cycling therapy can
reduce the development of resistance to one or more of the
therapies, avoid or reduce the side effects of one of the
therapies, and/or improves the efficacy of the treatment.
[0158] Consequently, in one specific embodiment of the invention, a
compound of this invention is administered daily in a single or
divided doses in a four to six week cycle with a rest period of
about a week or two weeks. The invention further allows the
frequency, number, and length of dosing cycles to be increased.
Thus, another specific embodiment of the invention encompasses the
administration of a compound of this invention for more cycles than
are typical when it is administered alone. In yet another specific
embodiment of the invention, a compound of this invention is
administered for a greater number of cycles that would typically
cause dose-limiting toxicity in a patient to whom a second active
ingredient is not also being administered.
[0159] In one embodiment, a compound of this invention is
administered daily and continuously for three or four weeks at a
dose of from about 1 to about 5,000 mg/d followed by a break of one
or two weeks. A compound of this invention is preferably
administered daily and continuously at an initial dose of 1 to 5
mg/d with dose escalation (every week) by 10 to 100 mg/d to a
maximum dose of 5,000 mg/d for as long as therapy is tolerated. In
a particular embodiment, the compound is administered in an amount
of about 400, 800, or 1,200 mg/day, preferably in an amount of
about 800 mg/day for three to four weeks, followed by one week or
two weeks of rest in a four or six week cycle.
[0160] In one embodiment of the invention, a compound of this
invention and a second active ingredient are administered orally,
with administration of a compound of this invention occurring 30 to
60 minutes prior to a second active ingredient, during a cycle of
four to six weeks. In another embodiment of the invention, the
combination of a compound of this invention and a second active
ingredient is administered by intravenous infusion over about 90
minutes every cycle. In a specific embodiment, one cycle comprises
the administration of from about 400 to about 800 mg/day of a
compound of this invention and from about 50 to about 200
mg/m.sup.2/day of a second active ingredient daily for 3 to 4 weeks
and then one or two weeks of rest. In another specific embodiment,
each cycle comprises the administration of from about 200 to about
400 mg/day of a compound of this invention and from about 50 to
about 200 mg/m.sup.2/day of a second active ingredient for three to
four weeks followed by one or two weeks of rest. Typically, the
number of cycles during which the combinatorial treatment is
administered to a patient will be from about one to about 24
cycles, more typically from about two to about 16 cycles, and even
more typically from about four to about eight cycles.
4.4 Pharmaceutical Compositions
[0161] Pharmaceutical compositions can be used in the preparation
of individual, single unit dosage forms. Pharmaceutical
compositions and dosage forms of the invention comprise a compound
of this invention. Pharmaceutical compositions and dosage forms of
the invention can further comprise one or more excipients.
[0162] Pharmaceutical compositions and dosage forms of the
invention can also comprise one or more additional active
ingredients. Consequently, pharmaceutical compositions and dosage
forms of the invention comprise the active ingredients disclosed
herein (e.g., a compound of this invention and optionally a second
active agent). Examples of optional second, or additional, active
ingredients are disclosed herein (see, e.g., section 4.2).
[0163] Single unit dosage forms of the invention are suitable for
oral, mucosal (e.g. nasal, sublingual, vaginal, buccal, or rectal),
parenteral (e.g., subcutaneous, intravenous, bolus injection,
intramuscular, or intraarterial), topical (e.g., eye drops or other
ophthalmic preparations), transdermal or transcutaneous
administration to a patient. Examples of dosage forms include, but
are not limited to: tablets; caplets; capsules, such as soft
elastic gelatin capsules; cachets; troches; lozenges; dispersions;
suppositories; powders; aerosols (e.g., nasal sprays or inhalers);
gels; liquid dosage forms suitable for oral or mucosal
administration to a patient, including suspensions (e.g., aqueous
or non-aqueous liquid suspensions, oil-in-water emulsions, or a
water-in-oil liquid emulsions), solutions, and elixirs; liquid
dosage forms suitable for parenteral administration to a patient;
eye drops or other ophthalmic preparations suitable for topical
administration; and sterile solids (e.g., crystalline or amorphous
solids) that can be reconstituted to provide liquid dosage forms
suitable for parenteral administration to a patient.
[0164] The composition, shape, and type of dosage forms of the
invention will typically vary depending on their use. For example,
a dosage form used in the acute treatment of a disease may contain
larger amounts of one or more of the active ingredients it
comprises than a dosage form used in the chronic treatment of the
same disease. Similarly, a parenteral dosage form may contain
smaller amounts of one or more of the active ingredients it
comprises than an oral dosage form used to treat the same disease.
These and other ways in which specific dosage forms encompassed by
this invention will vary from one another will be readily apparent
to those skilled in the art. See, e.g., Remington's Pharmaceutical
Sciences, 18th ed., Mack Publishing, Easton Pa. (1990).
[0165] Typical pharmaceutical compositions and dosage forms
comprise one or more excipients. Suitable excipients are well known
to those skilled in the art of pharmacy, and non-limiting examples
of suitable excipients are provided herein. Whether a particular
excipient is suitable for incorporation into a pharmaceutical
composition or dosage form depends on a variety of factors well
known in the art including, but not limited to, the way in which
the dosage form will be administered to a patient. For example,
oral dosage forms such as tablets may contain excipients not suited
for use in parenteral dosage forms. The suitability of a particular
excipient may also depend on the specific active ingredients in the
dosage form. For example, the decomposition of some active
ingredients may be accelerated by some excipients such as lactose,
or when exposed to water. Active ingredients that comprise primary
or secondary amines are particularly susceptible to such
accelerated decomposition. Consequently, this invention encompasses
pharmaceutical compositions and dosage forms that contain little,
if any, lactose other mono- or di-saccharides. As used herein, the
term "lactose-free" means that the amount of lactose present, if
any, is insufficient to substantially increase the degradation rate
of an active ingredient.
[0166] Lactose-free compositions of the invention can comprise
excipients that are well known in the art and are listed, for
example, in the U.S. Pharmacopeia (USP) 25-NF20 (2002). In general,
lactose-free compositions comprise active ingredients, a
binder/filler, and a lubricant in pharmaceutically compatible and
pharmaceutically acceptable amounts. Preferred lactose-free dosage
forms comprise active ingredients, microcrystalline cellulose,
pre-gelatinized starch, and magnesium stearate.
[0167] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising active ingredients, since
water can facilitate the degradation of some compounds. For
example, the addition of water (e.g., 5%) is widely accepted in the
pharmaceutical arts as a means of simulating long-term storage in
order to determine characteristics such as shelf-life or the
stability of formulations over time. See, e.g., Jens T. Carstensen,
Drug Stability: Principles & Practice, 2d. Ed., Marcel Dekker,
NY, N.Y., 1995, pp. 379-80. In effect, water and heat accelerate
the decomposition of some compounds. Thus, the effect of water on a
formulation can be of great significance since moisture and/or
humidity are commonly encountered during manufacture, handling,
packaging, storage, shipment, and use of formulations.
[0168] Anhydrous pharmaceutical compositions and dosage forms of
the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms that comprise lactose
and at least one active ingredient that comprises a primary or
secondary amine are preferably anhydrous if substantial contact
with moisture and/or humidity during manufacturing, packaging,
and/or storage is expected.
[0169] An anhydrous pharmaceutical composition should be prepared
and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions are preferably packaged using
materials known to prevent exposure to water such that they can be
included in suitable formulary kits. Examples of suitable packaging
include, but are not limited to, hermetically sealed foils,
plastics, unit dose containers (e.g., vials), blister packs, and
strip packs.
[0170] The invention further encompasses pharmaceutical
compositions and dosage forms that comprise one or more compounds
that reduce the rate by which an active ingredient will decompose.
Such compounds, which are referred to herein as "stabilizers,"
include, but are not limited to, antioxidants such as ascorbic
acid, pH buffers, or salt buffers.
[0171] Like the amounts and types of excipients, the amounts and
specific types of active ingredients in a dosage form may differ
depending on factors such as, but not limited to, the route by
which it is to be administered to patients. However, typical dosage
forms of the invention comprise a compound of this invention in an
amount of from about 0.10 to about 150 mg. Typical dosage forms
comprise a compound of this invention in an amount of about 0.1, 1,
2, 5, 7.5, 10, 12.5, 15, 17.5, 20, 25, 50, 100, 150 or 200 mg. In a
specific embodiment, a preferred dosage form comprises a compound
of this invention in an amount of about 5, 10, 25 or 50 mg. Typical
dosage forms comprise the second active ingredient in an amount of
1 to about 1000 mg, from about 5 to about 500 mg, from about 10 to
about 350 mg, or from about 50 to about 200 mg. Of course, the
specific amount of the anti-cancer drug will depend on the specific
agent used, the type of cancer being treated or managed, and the
amount(s) of a compound of this invention and any optional
additional active agents concurrently administered to the
patient.
4.4.1 Oral Dosage Forms
[0172] Pharmaceutical compositions of the invention that are
suitable for oral administration can be presented as discrete
dosage forms, such as, but are not limited to, tablets (e.g.,
chewable tablets), caplets, capsules, and liquids (e.g., flavored
syrups). Such dosage forms contain predetermined amounts of active
ingredients, and may be prepared by methods of pharmacy well known
to those skilled in the art. See generally, Remington's
Pharmaceutical Sciences, 18th ed., Mack Publishing, Easton Pa.
(1990).
[0173] Typical oral dosage forms of the invention are prepared by
combining the active ingredients in an intimate admixture with at
least one excipient according to conventional pharmaceutical
compounding techniques. Excipients can take a wide variety of forms
depending on the form of preparation desired for administration.
For example, excipients suitable for use in oral liquid or aerosol
dosage forms include, but are not limited to, water, glycols, oils,
alcohols, flavoring agents, preservatives, and coloring agents.
Examples of excipients suitable for use in solid oral dosage forms
(e.g., powders, tablets, capsules, and caplets) include, but are
not limited to, starches, sugars, micro-crystalline cellulose,
diluents, granulating agents, lubricants, binders, and
disintegrating agents.
[0174] Because of their-ease of administration, tablets and
capsules represent the most advantageous oral dosage unit forms, in
which case solid excipients are employed. If desired, tablets can
be coated by standard aqueous or nonaqueous techniques. Such dosage
forms can be prepared by any of the methods of pharmacy. In
general, pharmaceutical compositions and dosage forms are prepared
by uniformly and intimately admixing the active ingredients with
liquid carriers, finely divided solid carriers, or both, and then
shaping the product into the desired presentation if necessary.
[0175] For example, a tablet can be prepared by compression or
molding. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredients in a free-flowing form such
as powder or granules, optionally mixed with an excipient. Molded
tablets can be made by molding in a suitable machine a mixture of
the powdered compound moistened with an inert liquid diluent.
[0176] Examples of excipients that can be used in oral dosage forms
of the invention include, but are not limited to, binders, fillers,
disintegrants, and lubricants. Binders suitable for use in
pharmaceutical compositions and dosage forms include, but are not
limited to, corn starch, potato starch, or other starches, gelatin,
natural and synthetic gums such as acacia, sodium alginate, alginic
acid, other alginates, powdered tragacanth, guar gum, cellulose and
its derivatives (e.g., ethyl cellulose, cellulose acetate,
carboxymethyl cellulose calcium, sodium carboxymethyl cellulose),
polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch,
hydroxypropyl methyl cellulose, (e.g., Nos. 2208, 2906, 2910),
microcrystalline cellulose, and mixtures thereof.
[0177] Suitable forms of microcrystalline cellulose include, but
are not limited to, the materials sold as AVICEL-PH-101,
AVICEL-PH-103 AVICEL RC-581, AVICEL-PH-105 (available from FMC
Corporation, American Viscose Division, Avicel Sales, Marcus Hook,
Pa.), and mixtures thereof. An specific binder is a mixture of
microcrystalline cellulose and sodium carboxymethyl cellulose sold
as AVICEL RC-581. Suitable anhydrous or low moisture excipients or
additives include AVICEL-PH-103.TM. and Starch 1500 LM.
[0178] Examples of fillers suitable for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof. The binder or filler in pharmaceutical
compositions of the invention is typically present in from about 50
to about 99 weight percent of the pharmaceutical composition or
dosage form.
[0179] Disintegrants are used in the compositions of the invention
to provide tablets that disintegrate when exposed to an aqueous
environment. Tablets that contain too much disintegrant may
disintegrate in storage, while those that contain too little may
not disintegrate at a desired rate or under the desired conditions.
Thus, a sufficient amount of disintegrant that is neither too much
nor too little to detrimentally alter the release of the active
ingredients should be used to form solid oral dosage forms of the
invention. The amount of disintegrant used varies based upon the
type of formulation, and is readily discernible to those of
ordinary skill in the art. Typical pharmaceutical compositions
comprise from about 0.5 to about 15 weight percent of disintegrant,
preferably from about 1 to about 5 weight percent of
disintegrant.
[0180] Disintegrants that can be used in pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, agar-agar, alginic acid, calcium carbonate,
microcrystalline cellulose, croscarmellose sodium, crospovidone,
polacrilin potassium, sodium starch glycolate, potato or tapioca
starch, other starches, pre-gelatinized starch, other starches,
clays, other algins, other celluloses, gums, and mixtures
thereof.
[0181] Lubricants that can be used in pharmaceutical compositions
and dosage forms of the invention include, but are not limited to,
calcium stearate, magnesium stearate, mineral oil, light mineral
oil, glycerin, sorbitol, mannitol, polyethylene glycol, other
glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated
vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil,
sesame oil, olive oil, corn oil, and soybean oil), zinc stearate,
ethyl oleate, ethyl laureate, agar, and mixtures thereof.
Additional lubricants include, for example, a syloid silica gel
(AEROSIL200, manufactured by W. R. Grace Co. of Baltimore, Md.), a
coagulated aerosol of synthetic silica (marketed by Degussa Co. of
Piano, Tex.), CAB-O-SIL (a pyrogenic silicon dioxide product sold
by Cabot Co. of Boston, Mass.), and mixtures thereof. If used at
all, lubricants are typically used in an amount of less than about
1 weight percent of the pharmaceutical compositions or dosage forms
into which they are incorporated.
[0182] A preferred solid oral dosage form of the invention
comprises a compound of this invention, anhydrous lactose,
microcrystalline cellulose, polyvinylpyrrolidone, stearic acid,
colloidal anhydrous silica, and gelatin.
4.4.2 Delayed Release Dosage Forms
[0183] Active ingredients of the invention can be administered by
controlled release means or by delivery devices that are well known
to those of ordinary skill in the art. Examples include, but are
not limited to, those described in U.S. Pat. Nos. 3,845,770;
3,916,899; 3,536,809; 3,598,123; and 4,008,719, 5,674,533,
5,059,595, 5,591,767, 5,120,548, 5,073,543, 5,639,476, 5,354,556,
and 5,733,566, each of which is incorporated herein by reference.
Such dosage forms can be used to provide slow or controlled-release
of one or more active ingredients using, for example,
hydropropylmethyl cellulose, other polymer matrices, gels,
permeable membranes, osmotic systems, multilayer coatings,
microparticles, liposomes, microspheres, or a combination thereof
to provide the desired release profile in varying proportions.
Suitable controlled-release formulations known to those of ordinary
skill in the art, including those described herein, can be readily
selected for use with the active ingredients of the invention. The
invention thus encompasses single unit dosage forms suitable for
oral administration such as, but not limited to, tablets, capsules,
gelcaps, and caplets that are adapted for controlled-release.
[0184] All controlled-release pharmaceutical products have a common
goal of improving drug therapy over that achieved by their
non-controlled counterparts. Ideally, the use of an optimally
designed controlled-release preparation in medical treatment is
characterized by a minimum of drug substance being employed to cure
or control the condition in a minimum amount of time. Advantages of
controlled-release formulations include extended activity of the
drug, reduced dosage frequency, and increased patient compliance.
In addition, controlled-release formulations can be used to affect
the time of onset of action or other characteristics, such as blood
levels of the drug, and can thus affect the occurrence of side
(e.g., adverse) effects.
[0185] Most controlled-release formulations are designed to
initially release an amount of drug (active ingredient) that
promptly produces the desired therapeutic effect, and gradually and
continually release of other amounts of drug to maintain this level
of therapeutic or prophylactic effect over an extended period of
time. In order to maintain this constant level of drug in the body,
the drug must be released from the dosage form at a rate that will
replace the amount of drug being metabolized and excreted from the
body. Controlled-release of an active ingredient can be stimulated
by various conditions including, but not limited to, pH,
temperature, enzymes, water, or other physiological conditions or
compounds.
4.4.3 Parenteral Dosage Forms
[0186] Parenteral dosage forms can be administered to patients by
various routes including, but not limited to, subcutaneous,
intravenous (including bolus injection), intramuscular, and
intraarterial. Because their administration typically bypasses
patients' natural defenses against contaminants, parenteral dosage
forms are preferably sterile or capable of being sterilized prior
to administration to a patient. Examples of parenteral dosage forms
include, but are not limited to, solutions ready for injection, dry
products ready to be dissolved or suspended in a pharmaceutically
acceptable vehicle for injection, suspensions ready for injection,
and emulsions.
[0187] Suitable vehicles that can be used to provide parenteral
dosage forms of the invention are well known to those skilled in
the art. Examples include, but are not limited to: Water for
Injection USP; aqueous vehicles such as, but not limited to, Sodium
Chloride Injection, Ringer's Injection, Dextrose Injection,
Dextrose and Sodium Chloride Injection, and Lactated Ringer's
Injection; water-miscible vehicles such as, but not limited to,
ethyl alcohol, polyethylene glycol, and polypropylene glycol; and
non-aqueous vehicles such as, but not limited to, corn oil,
cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl
myristate, and benzyl benzoate.
[0188] Compounds that increase the solubility of one or more of the
active ingredients disclosed herein can also be incorporated into
the parenteral dosage forms of the invention. For example,
cyclodextrin and its derivatives can be used to increase the
solubility of a compound of this invention. See, e.g., U.S. Pat.
No. 5,134,127, which is incorporated herein by reference.
4.4.4 Topical and Mucosal Dosage Forms
[0189] Topical and mucosal dosage forms of the invention include,
but are not limited to, sprays, aerosols, solutions, emulsions,
suspensions, eye drops or other ophthalmic preparations, or other
forms known to one of skill in the art. See, e.g., Remington's
Pharmaceutical Sciences, 16.sup.th and 18.sup.th eds., Mack
Publishing, Easton Pa. (1980 & 1990); and Introduction to
Pharmaceutical Dosage Forms, 4th ed., Lea & Febiger,
Philadelphia (1985). Dosage forms suitable for treating mucosal
tissues within the oral cavity can be formulated as mouthwashes or
as oral gels.
[0190] Suitable excipients (e.g., carriers and diluents) and other
materials that can be used to provide topical and mucosal dosage
forms encompassed by this invention are well known to those skilled
in the pharmaceutical arts, and depend on the particular tissue to
which a given pharmaceutical composition or dosage form will be
applied. With that fact in mind, typical excipients include, but
are not limited to, water, acetone, ethanol, ethylene glycol,
propylene glycol, butane-1,3-diol, isopropyl myristate, isopropyl
palmitate, mineral oil, and mixtures thereof to form solutions,
emulsions or gels, which are non-toxic and pharmaceutically
acceptable. Moisturizers or humectants can also be added to
pharmaceutical compositions and dosage forms if desired. Examples
of such additional ingredients are well known in the art. See,
e.g., Remington's Pharmaceutical Sciences, 16.sup.th and 18.sup.th
eds., Mack Publishing, Easton Pa. (1980 & 1990).
[0191] The pH of a pharmaceutical composition or dosage form may
also be adjusted to improve delivery of one or more active
ingredients. Similarly, the polarity of a solvent carrier, its
ionic strength, or tonicity can be adjusted to improve delivery.
Compounds such as stearates can also be added to pharmaceutical
compositions or dosage forms to advantageously alter the
hydrophilicity or lipophilicity of one or more active ingredients
so as to improve delivery. In this regard, stearates can serve as a
lipid vehicle for the formulation, as an emulsifying agent or
surfactant, and as a delivery-enhancing or penetration-enhancing
agent. Different salts, hydrates or solvates of the active
ingredients can be used to further adjust the properties of the
resulting composition.
4.4.5 Kits
[0192] Typically, active ingredients of the invention are
preferably not administered to a patient at the same time or by the
same route of administration. This invention therefore encompasses
kits which, when used by the medical practitioner, can simplify the
administration of appropriate amounts of active ingredients to a
patient.
[0193] A typical kit of the invention comprises a dosage form of a
compound of this invention. Kits encompassed by this invention can
further comprise additional active ingredients such as oblimersen
(Genasense.RTM.), melphalan, G-CSF, GM-CSF, EPO, topotecan,
dacarbazine, irinotecan, taxotere, WFN, COX-2 inhibitor,
pentoxifylline, ciprofloxacin, dexamethasone, IL2, IL8, IL18,
Ara-C, vinorelbine, isotretinoin, 13 cis-retinoic acid, or a
pharmacologically active mutant or derivative thereof, or a
combination thereof. Examples of the additional active ingredients
include, but are not limited to, those disclosed herein (see, e.g.,
section 5.2).
[0194] Kits of the invention can further comprise devices that are
used to administer the active ingredients. Examples of such devices
include, but are not limited to, syringes, drip bags, patches, and
inhalers.
[0195] Kits of the invention can further comprise cells or blood
for transplantation as well as pharmaceutically acceptable vehicles
that can be used to administer one or more active ingredients. For
example, if an active ingredient is provided in a solid form that
must be reconstituted for parenteral administration, the kit can
comprise a sealed container of a suitable vehicle in which the
active ingredient can be dissolved to form a particulate-free
sterile solution that is suitable for parenteral administration.
Examples of pharmaceutically acceptable vehicles include, but are
not limited to: Water for Injection USP; aqueous vehicles such as,
but not limited to, Sodium Chloride Injection, Ringer's Injection,
Dextrose Injection, Dextrose and Sodium Chloride Injection, and
Lactated Ringer's Injection; water-miscible vehicles such as, but
not limited to, ethyl alcohol, polyethylene glycol, and
polypropylene glycol; and non-aqueous vehicles such as, but not
limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl
oleate, isopropyl myristate, and benzyl benzoate.
5. EXAMPLES
[0196] Certain embodiments of the invention are illustrated by the
following non-limiting examples.
5.1 2-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-cabamoyl-butyric
acid
##STR00010##
[0198] Step 1: To a suspension of
methyl-2-bromomethyl-3-nitrobenzoate (10.6 g, 39 mmol) and
L-glutamine t-butyl ester hydrochloride (9.2 g, 39 mmol) in THF (92
mL), was added TEA (12 mL) with stirring. The resulting mixture was
refluxed for 12 hours and then cooled to ambient temperature. The
mixture was concentrated to dryness, charged with water (100 mL)
and MTBE (100 mL). The slurry was stirred at ambient temperature
for 30 minutes. The solid was collected by vacuum filtration,
washed with 0.2 N aqueous HCl (30 mL), DI water (30 mL.times.2),
MTBE-(30 mL.times.3), and dried at 60.degree. C. in vacuo
overnight, giving 9.37 g (67% yield) of
4-carbamoyl-2-(4-notro-1-oxo-1,3-dihydro-isoindo-2-yl)-butyric acid
t-butyl ester as a white powder. .sup.1H NMR (DMSO-d.sub.6): 8.48
(d, 1H), 8.17 (d, 1H), 7.84 (t, 1H), 7.24 (s, 1H), 6.78 (s, 1H),
4.94 (s, 2H), 4.75-4.81 (m, 1H), 2.10-2.33 (m, 4H), 1.41 (s,
9H).
[0199] Step 2: TFA (47 mL) was added to a stirred slurry of
4-cabamoyl-2-(4-nitro-1-oxo-1,3-dihydro-isoindo-2-yl)-butyric acid
t-butylester (9.4 g, 26 mmol) in DCM (47 mL) at -15.degree. C. over
55 minutes. The mixture was stirred at -15.degree. C. for another 5
minutes after the addition of TFA. It was then allowed to warm to
ambient temperature and stirring was continued at ambient
temperature for an additional 5 hours. The reaction solution was
concentrated in vacuo, stirred with 95 mL of ethyl acetate at
ambient temperature for 16 hours. The solid was collected by vacuum
filtration, washed with EtOAc (10 mL.times.2), and dried in vacuo
at 60.degree. C. for 15 hours, affording 7.60 g (95% yield) of a
pale tan powder of
4-carbamoyl-2-(4-nitro-1-oxo-1,3-dihydro-isoindo-2-yl)-butyric
acid. .sup.1H NMR (DMSO-d.sub.6): 13.14 (brs, 1H), 8.47 (d, 1H),
8.17 (d, 1H), 7.84 (t, 1H), 7.22 (s, 1H), 6.75 (s, 1H), 4.94 (s,
2H), 4.78-4.84 (m, 1H), 2.11-2.37 (m, 4H).
[0200] Step 3:
4-Carbamoyl-2-(4-nitro-1-oxo-1,3-isoindo-2-yl)-butyric acid (9.8 g,
32 mmol), 10% Pd/C (1 g), methanol (150 mL), and DI water (50 mL)
were combined and shaken under 45-50 psi H.sub.2 for 6 hours at
ambient temperature. The reaction slurry was filtered through a
celite bed and the celite bed was washed with 80 mL of methanol.
The methanol wash and the filtrate were combined and concentrated
in vacuo to dryness. The residue was then dissolved in DI water
(200 mL), frozen in a dry-ice bath, and lyophilized for one week to
provide 8.30 g of an off-white solid
2-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric
acid in 90% yield: mp 158-160.degree. C.; .sup.1H NMR
DMSO-d.sub.6): 7.14-7.28 (m, 2H), 6.76-6.90 (m, 3H), 5.51 (brs,
2H), 4.71-4.77 (m, 1H), 4.16-4.32 (m, 2H), 1.90-2.32 (m, 4H)
(showed 0.1 mol of MeOH and 0.4 mol H.sub.2O); .sup.13C NMR
(DMSO-d.sub.6): 173.19, 172.55, 169.06, 143.64, 132.41, 128.81,
125.74, 116.32, 110.44, 53.22, 48.65 (MeOH), 45.26, 31.60, 24.96.
Analy. calculated for
C.sub.13H.sub.13N.sub.3O.sub.4--0.4H.sub.2O/0.1MeOH: 54.69% C,
5.68% H, 14.61% N, 2.5% H.sub.2O. Found: 55.05% C, 5.42% H, 14.39%
N, 3.6% H.sub.2O.
5.2 4-(4-Amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric
acid
##STR00011##
[0202] Step 1: To a suspension of
methyl-2-bromomethyl-3-nitrobenxoate (5.8 g, 21 mmol) and
L-isoglutamine t-butyl ester hydrochloride (5 g, 21 mmol) in THF
(50 mL), was added TEA (6.5 mL) with stirring. The resulting
mixture was refluxed for 24 hours and then cooled to ambient
temperature. The mixture was concentrated to dryness, charged with
water (75 mL) and MTBE (75 mL). The slurry was then stirred at
ambient temperature for 2 hours. The solid was collected by vacuum
filtration, washed with 0.2 N aqueous HCl (15 mL), DI water (20
mL.times.7 to neutral pH), and MTBE (20 mL). The wet cake was
further reslurried at ambient temperature for 16.5 hours in a
mixture of solvent containing MTBE (100 mL) and DI water (50 mL).
The solid was collected by vacuum filtration, washed with MTBE (65
mL), and dried at 60.degree. C. in vacuo for 15 hours, giving 5.30
g (70% yield) of
4-carbamoyl-4-(4-nitro-1-oxo-1,3-dihydro-isoindo-2-yl)-butyric acid
t-butyl ester as a pale tan powder. mp 174-176.degree. C.; .sup.1H
NMR (DMSO-d.sub.6): 8.45 (d, 1H), 8.16 (d, 1H), 7.82 (t, 1H), 7.64
(s, 1H), 7.27 (s, 1H), 4.98 (dd, 2H), 4.78 (dd, 1H), 2.00-2.25 (m,
4H), 1.33 (s, 9H); .sup.13C NMR (DMSO-d.sub.6): 171.49, 171.37,
165.81, 143.27, 137.80, 135.00, 129.91, 129.56, 126.73, 79.80,
53.75, 48.17, 31.65, 27.65, 24.83 ppm. Analy. calculated for
C.sub.17H.sub.31N.sub.3O.sub.6: 56.19% C, 5.83% H, 11.56% N. Found:
55.89% C, 5.53% H, 11.26% N.
[0203] Step 2: TFA (26 mL) was added to a stirred slurry of
4-carbamoyl-4-(4-nitro-1-oxo-1,3-dihydro-isoindo-2-yl)-butyric acid
t-butyl ester (5.2 g, 14 mmol) in DCM (26 mL) at -15.degree. C.
over 25 minutes. The mixture was stirred at -15.degree. C. for
another 5 minutes after the addition of TFA. It was then allowed to
warm to ambient temperature and stirring was continued at ambient
temperature for an additional 4 hours. The reaction solution was
concentrated in vacuo, stirred with 52 mL of ethyl acetate at
ambient temperature for 15 hours. The solid was collected by vacuum
filtration, washed with EtOAc twice (14+21 mL), and reslurried in
acetone (20 mL) at ambient temperature for 2 hours. The suspension
was filtered and the solid was washed with acetone (27 mL.times.2).
The solid was dried in vacuo at 60.degree. C. for 2 hours,
affording 4.17 g (95% yield) of
4-carbamoyl-4-(4-nitro-1-oxo-1,3-dihydro-isoindo-2-yl)-butyric acid
as a pale tan powder. mp 219-221.degree. C.; .sup.1H NMR
(DMSO-d.sub.6): 12.14 (brs, 1H), 8.46 (d, 1H), 8.16 (d, 1H), 7.82
(t, 1H), 7.67 (s, 1H), 7.29 (s, 1H), 5.00 (dd, 2H), 4.77-4.82 (m,
1H), 1.99-2.26 (m, 4H); .sup.13C NMR (DMSO-d.sub.6): 173.63,
171.65, 165.89, 143.31, 137.85, 135.00, 129.92, 129.59, 126.76,
53.78, 48.19, 30.58, 24.97. Analy. calculated for
C.sub.13H.sub.13N.sub.3O.sub.6.0.2H.sub.2O: 50.23% C, 4.34% H,
13.52% N, 1.2% H.sub.2O. Found: 50.23% C, 4.06% H, 13.23% N, 1.2%
H.sub.2O.
[0204] Step 3:
4-Carbamoyl-4-(4-nitro-1-oxo-1,3-dihydro-isoindo-2-yl)-butyric acid
(8.8 g, 29 mmol), 10% Pd/C (0.88 g), methanol (132 mL), and DI
water (44 mL) were combined and shaken under 45-50 psi H.sub.2 for
6 hours at ambient temperature. The reaction slurry was filtered
through a celite bed and the celite bed was washed with 75 mL of
methanol. The methanol wash and the filtrate were combined and
concentrated in vacuo to dryness. DI water (100 mL) was added to
the residue, and the mixture was again concentrated to dryness. The
residual oily material was then dissolved in DI water (200 mL),
frozen in a dry-ice bath, and lyophilized for 8 days to provide
7.30 g of
4-(4-amino-1-oxo-1,3-dihydro-isoindol-2-yl)-4-carbamoyl-butyric
acid as an off-white solid in 92% yield. mp 334-336.degree. C.;
.sup.1H NMR (DMSO-d.sub.6): 12.07 (brs, 1H), 7.54 (s, 1H),
6.76-7.20 (m, 4H), 5.42 (brs, 2H), 4.71-4.75 (m, 1H), 4.32 (dd,
2H), 1.90-2.22 (m, 4H); .sup.13C NMR (DMSO-d.sub.6): 173.62,
172.16, 168.84, 143.39, 132.48, 128.68, 126.06, 116.28, 110.53,
53.26, 45.31, 30.69, 25.09. Analy. calculated for
C.sub.13H.sub.15N.sub.3O.sub.4.0.2H.sub.2O: 55.59% C, 5.53% H,
14.96% N, 1.3% H.sub.2O. Found: 55.69% C, 5.30% H, 14.83% N, 1.4%
H.sub.2O.
5.3
4-Carbamoyl-4-[4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-iso-
indol-2-yl]-butyric acid
5.3.1 3-[(Furan-2-ylmethyl)-amino]-phthalic acid dimethyl ester
##STR00012##
[0206] To a stirred solution of 3-amino-phthalic acid dimethyl
ester (8.23 g, 39.32 mmol) in methylene chloride (200 ml) under a
nitrogen atmosphere, 2-furaldehyde (8.14 ml, 98.30 mmol) and acetic
acid (13.57 ml, 235.92 mmol) were added. The mixture was stirred
for 5 minutes, followed by addition of sodium triacetoxyborohydride
(25 g, 117.96 mmol). The reaction was stirred overnight, washed
with water (2.times.200 ml), saturated aqueous sodium bicarbonate
(2.times.200 ml), and brine (200 ml), and dried over MgSO.sub.4.
The solvent was evaporated in vacuo to give a brown oil (12.42 g),
which was used directly without purification.
5.3.2 3-[(Furan-2-yl-methyl)-amino]-phtalic acid
##STR00013##
[0208] To a stirred solution of crude
3-[(furan-2-yl-methyl)-amino]-phthalic acid dimethyl ester in
methanol (100 ml), was added 5N potassium hydroxide (79 ml). The
mixture was stirred at room temperature overnight. The solvent was
evaporated in vacuo and the residue dissolved in water (50 ml). The
water was washed with diethyl ether (2.times.100 ml). The aqueous
portion was cooled in an ice bath and the pH was adjusted to 2-3 by
dropwise addition of concentrated hydrochloric acid. The aqueous
solution was then extracted into ethyl acetate (3.times.100 ml).
The combined ethyl acetate extracts were washed with brine (150
ml), and dried over MgSO.sub.4. The solvent was evaporated in
vacuo, and the residue, which contained a mixture of diacid and
monomethyl esters, was used without further purification.
5.3.3 4-Carbamoyl-4-{4-[(furan-2-yl-methylamino]-1,3-dioxo
1,3-dihydro-isoindol-2-yl}-butyric acid
##STR00014##
[0210] To a stirred solution of
3-[(furan-2-yl-,ethyl)-amino]-phthalic acid (0.5 g, 1.93 mmol) in
pyridine (20 ml), was added 4-amino-4-carbamoyl-butyric acid (0.31
g, 2.12 mmol). The reaction mixture was heated to reflux overnight.
The solvent was evaporated in vacuo. The resulting residue was
dissolved in saturated sodium bicarbonate (50 ml) and washed with
ethyl acetate (2.times.50 ml). The aqueous portion was cooled in an
ice bath, and the pH was adjusted to 2-3 by dropwise addition of
concentrated hydrochloric acid. The aqueous solution was then
extracted into ethyl acetate (3.times.50 ml). The combined ethyl
acetate extracts were washed with brine (100 ml), and dried over
MgSO.sub.4. The solvent was evaporated in vacuo to give an oil. The
oil was purified by flash column chromatography (60% ethyl
acetate/39% hexane/1% formic acid) to give an oil, which was
triturated in diethyl ether (30 ml). The resulting yellow solid was
filtered and dried (0.14 g, 20%): mp 120-122.degree. C.; .sup.1H
NMR (DMSO-d.sub.6) .delta. 12.09 (s, 1H), 7.59-7.62 (m, 3H), 7.15
(d, J=8.25 Hz, 2H), 7.03-6.93 (m, 2H), 6.41-6.36 (m, 2H), 4.56-4.50
(m, 3H), 2.40-2.17 (m, 4H); .sup.13C NMR (DMSO-d.sub.6) .delta.
173.57, 170.04, 169.36, 167.71, 152.07, 145.57, 142.41, 135.60,
132.55, 116.99, 110.70, 110.46, 110.42, 107.41, 51.73, 30.66,
23.52; Analy. Calculated for C.sub.18H.sub.17N.sub.3O.sub.6: C,
57.25; H, 4.72; N, 11.13 (+0.35H.sub.2O). Found: C, 57.50; H, 4.59;
N, 10.93.
5.4
4-Carbamoyl-2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-iso-
indol-2-yl}-butyric acid
##STR00015##
[0212] 2-Amino-4-carbamoyl-butyric acid (0.31 g, 2.11 mmol) was
treated using the procedures substantially the same as those
described in Section 5.3, above, for the synthesis of
4-carbamoyl-2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoind-
ol-2-yl}-butyric acid. The residue was purified by flash column
chromatography (66% ethyl acetate/33% hexane/1% formic acid) to
give an oil (0.44 g). Further purification by preparative reverse
phase HPLC (38% acetonitrile/62% water, isocratic) provided an oil,
which was triturated in diethyl ether (30 ml). The resulting yellow
solid was filtered and dried (0.31 g, 44%): mp 114-116.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 13.14 (s, 1H), 7.59-7.54 (m,
2H), 7.19-7.16 (m, 2H), 7.05-6.97 (m, 2H), 6.70 (s, 1H), 6.41-6.36
(m, 2H), 4.64 (dd, J=4.49 Hz and J=10.49 Hz, 1H), 4.55 (d, J=6.01
Hz, 2H), 2.42-2.17 (m, 2H), 2.14-2.02 (m, 2H); .sup.13C NMR
(DMSO-d.sub.6) .delta. 173.03, 170.61, 169.06, 167.48, 151.99,
145.72, 142.44, 135.94, 132.13, 117.39, 110.89, 110.43, 109.79,
107.43, 50.93, 31.35, 24.02, 15.14; Analy. Calculated for
C.sub.19H.sub.17N.sub.3O.sub.6: C, 57.38; H, 4.71; N, 11.15
(+0.30H.sub.2O). Found: C, 57.00; H, 4.85; N 10.83.
5.5
2-{4-[(Furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}4-
-phenylcarbamoyl-butyric acid
##STR00016##
[0214] 2-Amino-4-phenylcarbamoyl-butyric acid (0.49 g, 2.20 mmol)
was treated according to the procedures substantially the same as
those described in Section 5.3, above, for the synthesis of
2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-4-p-
henylcarbamoyl-butyric acid. The residue was purified by flash
column chromatography (45% ethyl acetate/54% hexane/1% formic acid)
to provide a yellow solid (0.48 g, 53.6%): mp 146-148.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 13.13 (s, 1H), 9.81 (s, 1H),
7.59-7.38 (m, 4H), 7.26-7.14 (m, 3H), 7.04-6.96 (m, 3H), 6.40-6.34
(m, 2H), 4.71 (dd, J=3.80 Hz and J=9.50 Hz, 1H), 4.54 (d, J=5.95
Hz, 2H), 2.46-2.22 (m, 4H); .sup.13C NMR (DMSO-d.sub.6) .delta.
170.51, 169.95, 169.05, 167.46, 151.99, 145.73, 142.42, 139.07,
135.93, 132.12, 128.50, 122.88, 119.01, 117.39, 110.91, 110.43,
109.80, 107.39, 50.78, 32.75, 23.97; Analy. Calculated for
C.sub.24H.sub.21N.sub.3O.sub.6: C, 63.63; H, 4.81; N, 9.28
(+0.31H.sub.2O). Found: C, 63.38; H, 4.84; N, 9.20.
5.6
2-[4-[(Furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl]--
pentanedioic acid
##STR00017##
[0216] 2-Amino-pentanedioic acid (0.32 g, 2.18 mmol) was treated
using procedures substantially the same as those described in
Section 5.3, above, for the synthesis of
2-{4-[(furan-2-yl-methyl)-amino]-1,3-dioxo-1,3-dihydro-isoindol-2-yl}-pen-
tanedioic acid. The residue was purified by flash column
chromatography (42.5% ethyl acetate/56.5% hexane/1% formic acid) to
provide a yellow solid (0.54 g, 73%): mp 150-152.degree. C.;
.sup.1H NMR (DMSO-d.sub.6) .delta. 12.62 (s, 2H), 9.81 (s, 1H),
7.60-7.54 (m, 2H), 7.17 (d, J=8.58 Hz, 1H), 7.05-6.98 (m, 2H),
6.41-6.36 (m, 2H), 4.72 (dd, J=4.10 Hz and J=9.80 Hz, 1H), 4.56 (d,
J=6.05 Hz, 2H), 2.38-2.20 (m, 4H); .sup.13C NMR (DMSO-d.sub.6)
.delta. 173.59, 170.47, 169.04, 167.46, 151.98, 145.74, 142.42,
135.94, 132.10, 117.42, 110.93, 110.42, 109.77, 107.40, 95.55,
50.55, 30.29, 23.69; Analy. Calculated for
C.sub.18H.sub.16N.sub.2O.sub.7: C, 57.40; H, 4.40; N, 7.40
(+0.17H.sub.2O+0.02 EtOAc+0.02 CH.sub.2Cl.sub.2). Found: C, 57.01;
H, 4.18; N, 7.27.
5.7 Cyclopropanecarboxylic acid
{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-[1,3,4]oxadiazol-2-yl-ethyl]-3-oxo-2,-
3-dihydro-1H-isoindol-4-yl}-amide
##STR00018##
[0218] Cyclopropanecarboxylic acid
{2-[1-(3-ethoxy-4-methoxy-phenyl)-2-[1,3,4]oxadiazol-2-yl-ethyl]-3-oxo-2,-
3-dihydro-1H-isoindol-4-yl}-amide was prepared by reacting
3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-3-(3-e-
thoxy-4-methoxy-phenyl)-propionic acid (400 mg, 0.9 mmol), CDI (160
mg, 1.0 mmol) and formic hydrazide (0.09 g, 1.5 mmol) in THF (5
mL). The crude was then reacted with phosphorus oxychloride (0.18
mL, 1.9 mmol) in acetonitrile (15 mL). The product was obtained as
a white solid (60 mg, 15% yield): mp 181-183.degree. C.; .sup.1H
NMR (CDCl.sub.3) .delta. 0.86-0.92 (m, 2H, cyclopropyl CH.sub.2),
1.06-1.11 (m, 2H, cyclopropyl CH.sub.2), 1.45 (t, J=7.5 Hz, 3H,
CH.sub.3), 1.58-1.68 (m, 1H, cyclopropyl CH), 3.66 (dd, J=5, 15 Hz,
1H, CHH), 3.85 (dd, J=10, 15 Hz, 1H, CHH), 3.87 (s, 3H, CH.sub.3),
4.03-4.11 (m, 3H, OCH.sub.2CH.sub.3+CHH), 4.43 (d, J=17 Hz, 1H,
CHH), 5.86-5.91 (m, 1H, NCH), 6.85-6.90 (m, 2H, Ar), 6.96-7.01 (m,
2H, Ar), 7.43 (t, J=7.5 Hz, 1H, Ar), 8.35 (s, 1H, Ar), 8.41 (d,
J=7.5 Hz, 1H, Ar), 10.41 (s, 1H, NH); .sup.13C NMR (CDCl.sub.3) ,
8.27, 8.29, 14.73, 16.16, 28.04, 46.36, 52.26, 55.98, 64.64,
111.53, 112.36, 116.80, 116.96, 117.80, 119.16, 129.54, 133.43,
138.06, 141.25, 148.84, 149.64, 153.34, 163.79, 169.50, 172.66.
Analy. calculated for C.sub.25H.sub.25N.sub.4O.sub.5+0.1H.sub.2O:
C, 64.47; H, 5.69; N, 12.07. Found: C, 64.50; H, 5.70; N,
11.69.
5.8 Inhibition of MM Cell Proliferation
[0219] The ability of a compound of this invention to effect the
proliferation of multiple myeloma (MM) cell lines is investigated
in an in vitro study. Uptake [.sup.3H]-thymidine by different MM
cell lines (MM. IS, Hs Sultan, U266 and RPMI-8226) is measured as
an indicator of cell proliferation. Cells are incubated in the
presence of compound for 48 hours; [.sup.3H]-thymidine is included
for the last 8 hours of the incubation period.
5.9 In Vivo LPS-Induced TNF-.alpha. Production Assay
[0220] Male CD rats procured from Charles River Laboratories at
seven weeks of age are allowed to acclimate for one week prior to
use. A lateral tail vein is cannulated percutaneously with a
22-gage over-the-needle catheter under brief isoflurane anesthesia.
Rats are administered a compound of this invention either by
intravenous injection via the tail vein catheter or oral gavage 15
to 180 min prior to injection of 0.05 mg/kg LPS (E. Coli 055:B5).
Catheters are flushed with 2.5 mL/kg of normal injectable saline.
Blood is collected via cardiac puncture 90 minutes after LPS
challenge. Plasma is prepared using lithium heparin separation
tubes and frozen at -80.degree. C. until analyzed. TNF-.alpha.
levels are determined using a rat specific TNF-.alpha. ELISA kit
(Busywork). The ED.sub.50 values are calculated as the dose of the
compound of this invention at which the TNF-.alpha. production is
reduced to 50% of the control value.
5.10 Cycling Therapy in Patients
[0221] In a specific embodiment, a compound of this invention are
cyclically administered to patients with cancer. Cycling therapy
involves the administration of a first agent for a period of time,
followed by a rest for a period of time and repeating this
sequential administration. Cycling therapy can reduce the
development of resistance to one or more of the therapies, avoid or
reduce the side effects of one of the therapies, and/or improves
the efficacy of the treatment.
[0222] In a specific embodiment, prophylactic or therapeutic agents
are administered in a cycle of about four to six weeks, about once
or twice every day. One cycle can comprise the administration of a
therapeutic on prophylactic agent for three to four weeks and at
least one week or two weeks of rest. The number of cycles
administered is from about one to about 24 cycles, more typically
from about two to about 16 cycles, and more typically from about
four to about eight cycles.
5.11 Clinical Studies in Patients with Relapsed Multiple
Myeloma
[0223] Patients with relapsed and refractory Dune-Salmon stage III
multiple myeloma, who have either failed at least three previous
regimens or presented with poor performance status, neutropenia or
thrombocytopenia, are treated with up to four cycles of combination
melphalan (50 mg intravenously), a compound of this invention
(about 1 to 5,000 mg orally daily), and dexamethasone (40 mg/day
orally on days 1 to 4) every four to six weeks. Maintenance
treatment consisting of daily a compound of this invention and
monthly dexamethasone are continued until the disease progression.
The therapy comprising the administration of a compound of this
invention in combination with melphalan and dexamethasone is highly
active and generally tolerated in heavily pretreated multiple
myeloma patients whose prognosis is otherwise poor.
[0224] The embodiments of the invention described above are
intended to be merely exemplary, and those skilled in the art will
recognize, or will be able to ascertain using no more than routine
experimentation, numerous equivalents of specific compounds,
materials, and procedures. All such equivalents are considered to
be within the scope of the invention and are encompassed by the
appended claims.
[0225] All of the patents, patent publications and references cited
herein are incorporated in their entirety by reference. However,
citation of such references do not constitute an admission that
such references are prior art. This invention can be better
illustrated by the following claims.
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